Nanosoma-usofa.com

1. This entire article is not an official statement of any Nano Soma executive. As a global restoration research advisor to executives for 50 years: my discovery of the discoveror of Nano Soma, demands the most democratic distribution model.
2. Trump & Jackie Chan say the world needs the best hygiene in the form of good soap; Nano Soma has prevented and stopped covid, ebola, malaria in every scientific study; since it washes every human cell from within, deleting anything that’s non native to the intrinsic super immunity and sovereign in any properly treated human cell.
3. The presidents of two superpower countries started privately using Nano soma on 12/7/2020, based on the advice of their teams of medical doctors and top level labs. we hope they will go public in January with that; however they may not; and we will maintain their privacy, until further notice. NANO SOMA has been shown to inhibit SARS-COV-2 viral entry by blocking TMPRSS2 and ACE2 receptor in vitro and has been demonstrated to protect SARS-COV-2 positive patients in 3 to 5 days.
4. A Mumbai hospital trial of 30 COVID-19 positive patients confirmed by the Medical Superintendent – 75% cleared within 4 days. Click on link to read the letter from Municipal Corporation of Greater Mumbai, Conducted by dr.Chandra pawar in the kasturba hospital in Mumbai, population 20 million.
   http://nanorxeurope.com/Documents/India-hospital-letter.pdf. Many individuals have treated themselves for COVID-19 symptoms – http://testimonials.thenanosoma.com
   
5. Dear Mother Earth Guardian, as a fellow earth keeper and cancer victor, I’m sharing a photo remediation remedy to immunize and optimize every human cell in this global wellness phase transition.We bio mimic the environmental cleanup power of hemp with a patent, nano sized plant molecule, sublingual spray that stopped covid for over 30 hospital patients in 3 days in a professional scientific study. My affiliate Id is magicdichol.com/store/mdusa/?aff_id=4509 .
6. Our friend Karen had the vision on the gateway date to be a distributor and get a 40% discount on her purchase of 24 bottles. This discount is normally only for purchasing 60 bottles.The Affiliate program is 10% referral commission. There is no upfront cost to be an Affiliate and to purchase 1 bottle the price is $51 net of the referral commission. White label discount is negotiable. As a cell wellness student of 40 years, Karen observes, Nano Soma may be the single best way to stop and prevent any infectious virus or agent while simultaneously amending any cell wellness challenge for any condition, potentially in as little as 3 months of daily usage.Cell wellness author, Bruce Lipton, envisioned molecule x-a missing link to human evolution and wellness in all forms. Nano Soma may be that and far more in this pivotal moment in time, for all earth’s inhabitants. In vitro studies show Nano Soma may replicate and activate the entire genome and its immeasurable immunity collective collaborative intelligence which may surpass any computer of any kind. Nano contaminants of all kinds in all cells may be gently remediated as the collective wisdom of each cell in the body adds to the new civilization of the regeneration of the human ecosystem.Nano Soma has shown to be more pain relieving than morphine, more legal and illegal drugs are taken for pain and harmony deficiency in the physical and emotional body even after 6 generations; 120 years.2022 may see a crescendo of food shortage yet anecdotals show Nano Soma users eat up to ½ the food they used to after an average of 1 year of normal use. Resting heart rate studies show unparalleled heart efficiency and longevity much greater life quality extension, life spans of 150 to 180 may be the true normal, not synthetically medicating, billions of people, as planned by 2023.Repecting all life value molecule, naturally occurring and or synthetic, be they vitamin, minerals, plant or variations of carbon, oxygen, nitrogen, etc.; Nano Soma may be the most complimentary alternative medical molecular manna in the entire history of all life on earth.A leading bioform atic lab carried out studies on the effect of nano soma on human monocytes (THP1 Cells) and sequenced and identified over 2300 genes expressed. One conclusion was that nano soma interacts with all 48 nuclear receptors at various times over a 48 hour period.The world’s record for fastest patent acceptance is by Tesla and Thomas Edison, our patent was accepted in 1 months after it appeared as a patent application in September 2018.NASA says the mitochondria, each cells power station, are 80% lost by age 67, compared to the amount in a 25 year old.Much is said about the CoQ10, paw and other molecule; yet Nano Soma may regenerate mitochondria up to 100% at any age. We induce super activation of macrophages in 1-10 picograms that machine learn to engulf and recycle pathogenic and apoptotic cells. Autophagy is the cell recycling process. Apoptotic cells are those lost by adults up to 70 billion daily and up to 30 billion daily by those age 8-14.
7. While you wait for a no guarantee ever from any synthetic inoculation providers on the first of many, likely to be mandatory; prevention and treatment miracle injection, surveillance modern matrix, you may vote for an innocuous option by trying Nano Soma. See Webster’s innocuous and inoculation.
8. See the medical hospital covid overstudy with 30 patients in 3 days and risk a vote for the inauguration of all nations natural immunization with no sterilization and genome centralization. We may present and future insure present and future wellness with a stimulus check tsunami that collects compound cellular health wealth forever. The Nano Soma patents were granted faster than any US patent since 1791.
9. 2020 America encountered a pandemic,Econ-racial divide combo for the first time.Those 3 branches of the nation’s body are symptoms of bio cellular immune deficiency that may find one nano remedy.Bonds have brought nations to freedom and financed the American continental railroad and the Panama Canal.Post pandemic  immunity community assurance;is the self evident,evolution of the only inflation free ,currency;a naturally healthy population.
10. Park systems,a sub nano metrics analysis ,ca. firm,has a million dollar grant for North American nano labs.ideally, nano soma may be made from American sugar cane in a nano metric lab for vaccine scale,mass adoption,mega benefits. Mass adoption education warp speed benefits for this experience evidence based rollout were seeded on the 2/1,first of “Ten Commandments “press series for true ,new ,modern manna dispensation with the vision of 7 generation all nations compensation restoration and a nature given cellular sovereign all nations.Covid over and post pandemics,nature science ;intrinsically has no adversaries;only the uniformed;we stand ready to inform;as they choose.The data tsunami of the super immunity science has few doubting Thomas types ;and new validation and 1000 anecdotals arrives weekly.Status quo media will be your last resort source for this 360 human regeneration science for a global safe climate based on mass regeneration of next steps in human evolution for a economy and global culture that’s local,fair and exponentially dynamic.The tiny yet mighty ,millennium,tipping point may be as little as 10% of 3% of any community,consistently using a patented,anti viral,nano organic.sub lingual spray,for $2 a day;that’s been commercially available for 6 years,in full compliance with national regulatory agencies.Text only 936-718-2747,for all professional enquiries and the covid Ebola over 3rd part study and the 1/28-28, global wellness inauguration telethon with 13 licensed health professionals from 3 continents.Like the data breach,found by fire eye;our bio nano secures all bio data ;with 24/7 upgrades,in real time.An M.I.T.,PHD,after 12 years r&d ,says glycophosphate molecules overwhelm respiratory immunity,disrupting the innate immune component and imbalancing the adaptive side,preventing homeostasis and make a stimulus check for category 5,cytokine storms,electing unfriendly viral takeovers of people,nations and the planet.Postpandemics science is proven,safe,affordable and easily distributed on the scale needed,for super human immunity and all round health with no interference with any pharmaceutical prescriptions.For extreme validation see Jennifermargullis.netContaminated populations choose more contaminated paths when all cells are not well. Community immunity via our patented organic sublingual spray has high wire highest priority in California, Texas, New York and Florida as of 1/25. See npr.org. The 2009 virus was the 21st century’s first pandemic and this flu strain is still a seasonal virus.the bradkinin molecule is the eyes of the covid cytokine storm.See the online article on Mosaic-networx.com;this is why video is the most engaging type of content nanosoma volunteers may use.
11. Message to Del Bigtree Dear Del, I and Eddy Taylor, whom you may recall from Dr. Sandra Rose’s introduction, admire the Kennedy human rights legacy and your Highwire shows.We are familiar with the Mikki Willis Plandemic documentary series that had 2 billion viewers in 10 days and Dr. David  Martin has become a friend and a user of NANO SOMA.We are custodians of a surprising contribution representing unprecedented keys to worldwide wellness – see www.thenanosoma.com on the scale of safety, efficacy and  affordability for our world’s 8 billion people.Get the missing chapter from us after you see  our triumphant COVID-19 defeating and cellular sovereignty; clinicals on the site. Del, there is no human health condition that NANO SOMA does not trigger the body to heal,  and we fully expect that it will trigger the healing of RFK Jr’s Spasmodic Dysphonia.What a gift that would be to him and to the world!!! NANO SOMA produces 52 genes that relate to this condition and given he is in Westchester county, NY state Dr. Raghavan (Raghu), can send samples to him within hours. We’d like to make the developer of NANO SOMA, Dr. Palayakotai Raghavan available for your  Highwire program. Del, it is no accident that NANO SOMA is emerging into the world now, in the middle of this COVID-19 psyop.Please get back to me and help awaken the world to this piece of natural magic.Richard
12. Letter for Robert F Kennedy Jr.Dear Robert,I want to share with you a piece of natural magic – a nutraceutical made from food that has triggered the body to heal every human health condition against which it has been tested. This sounds impossible; however, when you understand that it is older than the oldest biological cell on this planet and has been intimately connected to all life, just hidden and then lost to humanity, its action becomes more understandable. Our bodies already know it. You have rightly spoken out on vaccination, in general and especially on its impact on our children. This product, NANO SOMA, can put an end to vaccination, including the COVID-19 global program currently being rolled out.NANO SOMA has been shown to treat SARS-COV-2 in vitro (https://www.researchsquare.com/article/rs-34021/v5) and in vivo (http://nanorxeurope.com/Documents/India-hospital-letter.pdf), and we have many testimonials from people who have treated themselves for COVID-19 using this product http://testimonials.thenanosoma.com.You can find details of NANO SOMA at www.thenanosoma.com. It has been shown to eliminate 17 other pathological viruses, including Zika, Ebola and many others. It also treats malaria. Here is the confirmation http://magicdichol.com/Brochures/NANO%20SOMA%20Hospital%20Letter%20treating%20TB.pdf that NANO SOMA treats TB.Type I and II diabetes are also treated. The treatment for any existing health condition is the same: usage-protocol.thenanosoma.com. This will handle everything except COVID-19 or similar, for which the protocol is 5 sprays every 4 hours until it’s cleared, usually 2-3 days. And the antibodies appear in 2 to 4 days, not 21 to 28, which I understand is the normal term.Remember that there has not yet been a health problem that has not been shown to cause the body to heal. None. Note that it replaces vitamin D by activating the vitamin D receptor (VDR), but it also de-regulates the VDR if it is overactive. Unheard of. Thus, it REGULATES the VDR. This means that it deals with TNF Alpha, the key to Parkinson’s, ALS and other conditions, and prevents a cytokine storm. And it interacts with all of the 48 nuclear receptors and has been demonstrated to regulate 22 of them, and its developer, Dr. Palayakotai Raghavan (Raghu), believes that it may regulate all of them. It also stimulates the body to produce its own endogenous vitamin C.Robert, there is no human health condition that NANO SOMA does not trigger the body to heal, and we fully expect that it will trigger the healing of your Spasmodic Dysphonia. What a gift that would be to you and to the world!!! NANO SOMA produces 52 genes that relate to this condition. Please see the table below.Given you are in Westchester county, NY state, Raghu can have samples to you in hours. Please get back to me and help awaken the world to this piece of natural magic.Kind Regards,Dr. RichardPresserrichard@magicdichol.com+1 (410) 500-4547
13. Testimonial from Dr. Howard Wolin My name is Howard Wolin. I am currently 79 years of age. I started out as a medical doctor. The training I had was as an intern and resident. The resident was in psychiatry in Chicago at what was then an incredible psychoanalytic training center and the guy who ran it was trained by Freud. In those days that was psychoanalytic psychotherapy – we actually talked to people and helped them deal with their stuff and then I went into practice at age 30 and started working with people in and out of the hospital – adolescents, geriatric patients with all sorts of psychiatric illnesses – psychosis, depressions, and then at the age of 36 I started, while I was practicing, a psychoanalytic training program concomitant with my practice and became a psychoanalyst at the age of 40 or 41. That involved seeing patients on the couch for about five days/week. That went on till I was about 50 but in my mid-40s – and actually in my 30s – I started a healing path, which started on the outside and got more and more deep, with seminars and experience-based learning from colleagues who were very much smarter than At the age of 50, I started a holistic practice. I shifted out of the psychoanalytic work into holistic practice; just functional medicine, functional bloodwork, kinesiology for testing for supplements. At that point, also, I started working spiritually; first with one colleague and then in the last 20-25 years with a native American tribe who have 3 or 4 reservations here in the States and a presence in Tibet, and I did the holistic work until 2012, retired, and then I’m still doing the spiritual work and working with friends and people close to me to use the kinesiology to help heal physical stuff with supplementation. When I test anything and likewise when I test a supplement for a patient, or when I test whether somebody should marry someone or whether they should get a job or whether they should hire someone, the baseline test is 100%. Right? 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%. Or if I test a supplement, if anything tests lower than 70%, I don’t want to use it. If I test a food, a coffee, anything else, I hold it against my body in a certain way that we test, and if it doesn’t test well, we don’t do it. So, when I tested Metadichol in the ways that I can test it, it literally tested – and I have confirmed this with colleagues who are at it as long as I – it tested a trillion percent positive,which is really pretty phenomenal. At times it’s tested higher in different venues. I have no doubt about the quality and the frequency of this is so, so high that, whatever it’s doing,whether it’s Raghu’s explanation about the Godfather, or it’s mine or anyone else’s, it really hasan incredibly high frequency.Here’s what I’m finding – using years of kinesiology experience and Metadichol as a filter or door opener, I’m finding that it unlocks/makes visible to the body’s consciousness deeply hidden chemicals – pesticides, ie Kepone and heavy metals hidden in and compromising the functioning of mitochondrial DNA – of glands, organs, neuronal tissue – ie thyroid, alveoli,bronchioles, spleen, renal tubules, liver, small intestine.It opens the door for the body mind to recognize the toxins – and once recognized – ie not hidden, the body dumps/detoxes it, thus allowing mitochondria to function more effectively with full energetic expression.But I have seen over 30 or 40 years and have done what I can to get rid of a whole host of polioviruses that were grown in chimpanzees. What I’m about to say to you is, since I’ve been usingMetadichol, they have in the last month to 2 months, they have gone from the RNA protein orthe DNA protein or mutated – those are the 3 forms – into now dead viruses. And it’s not justthat, it’s old mutated stuff – Hemolytic B, it’s smallpox, it’s varicella first starting out live, then mutated, then dead, so it does do that.It’s not the Godfather that tells the cells to shape up their asses; the cells have an enormousconsciousness. I think what it does is it shines the light on all the shit. And I’m finding it’s not just viral or bacterial, it’s every single toxin, including radioactive Strontium 90, which I got a huge dose of as a kid in New York and it’s including all sorts of heavy metals and it’s including all sorts of pesticides. I think what it does is it shines the light, opens the door to the cell seeing them, and then the cell knows already because they’re all conscious, to get rid of it and sweep it out. That’s my take. I could be wrong but that’s my take on it. It makes the crap visible.Let me give you one example. I have a massive menu but the menu has histological points, Gamma 2 which are called neurological points and all sorts of other body points. Over many years but especially over the last few months there’s been a huge amount of stuff clearing out of my liver as other places clear; and I’m working two days ago and suddenly the word sinusoid comes up. What it is, it’s not even a capillary. It’s tinier than a capillary and it’s in the liver, it’s in the adrenals, it’s in the bone marrow and all sorts of sinusoids start showing up. But, importantly, all sorts of toxic crap of the same sort that I’ve found shows up there, and the wayI do it is, when it’s recognized by me, through the menu, I write it down on a paper, I hold the paper with the writing facing out, I tap the body and the body is going to start dumping it like crazy. How do I know that? I know it but I have an incredible physical therapist who, when I’m working and she works she’ll see all sorts of either toxins or infections pouring out.But here’s the other interesting piece. The body hides things so that it can seal it around and protect it until it’s ready to let it go. And if it lets it go in one place, it lets it go in other places.So, Strontium 90 now is coming out from all over. But the interesting and fascinating thing about Metadichol – Raghu speaks about five sprays and I don’t doubt the science of his genius, but I have variously tested anywhere from five sprays once/day when I started; now I’m at a point where I can be testing at times 50 sprays five times/day and now 75 once/day; yesterday and the day before, 65 twice/day, and I trust my testing and something is going on where the body is saying that’s what I need to get rid of whatever this shit is. So, I’m putting this out there, not to dispute him but to suggest to you is that it really could be a lot different, depending on the day, the moment and what’s being dealt with. Now, this could just be my vehicle that needs, whatever it needs to do what it does.And I said this to you when I met you; I’ve been at this with supplements, and this is the best thing that will fix anything in the world. All the supplements I’ve taken are target specific, and there’s a company called SpectraCell that I use for the consult for over 30 years, least amount of supplements with the most effect; you can’t easily, palpably see what a supplement does.You can’t say, “Oh, my God, it’s like the movie “Paul” – he touches her in the eye and her eye heals instantly.”And most people, when they have this; I can see it in a way that other people really can’t see it.I can see what it’s doing, I can see what’s happened to my energy, my runs are better, I’m calmer in many ways. I mean there’s a lot of things that it does. I can see what it does inside interms of helping stuff, clearing stuff out. Mostly it’s my intent but this is the helper.Beyond amazing – after years of bullshit, this is something beyond real.Howard March, 2020
14. CHAPPAQUA, N.Y. – OhioPen — Metadichol®, a nano lipid formulation of long-chain alcohols, has been shown in vitro studies to be an anti-viral for SARS-COV-2 (the COVID-19 virus) and it does so by blocking the cell entry points for SARS-COV-2. The receptor ACE2 is used by the virus for entry and the serine protease TMPRSS2 for S protein priming.  It inhibits both ACE2 and TMPRSS2. An anti-viral assay against the virus using CACO2 cells showed that it had an EC90 of 0.16 µg/ml, which means it effectively eliminates the virus at a very low concentration.Metadichol® inhibits TMPRSS2 (EC50 of 96 ng/ml).
    It is 270 times more potent than another well-known inhibitor Camostat mesylate, which has EC50 of (26000 ng/ml). Metadichol is also a moderate inhibitor of ACE2 with an EC50 of 31 µg/ml. Moderate inhibition of ACE2 allows it to perform its key functions in the body, yet fend off SARS-COV-2 entry to the cell. ACE2 lowers blood pressure, regulates intestinal neutral amino acid transport. ACE2 expression and function is increasingly recognized as a potential therapeutic strategy in hypertension and cardiovascular disease, diabetes, lung injury, and fibrotic disorders. Metadichol, by binding to the Vitamin D receptor (VDR), acts on proteases like Furin and Adam-17, which activate the S-protein spikes for viral spread and pathogenesis in the infected hosts. In Malaria, CD147, also known as Basigin, is used by parasites to gain entry into the cell. Recent publications suggest that it also can be used as a point of entry by the SARS-COV-2 virus. Our previous work (US patent 9,006,292) showed that Metadichol is also potent against Malarial parasites and, by association, CD147. All these results and others are documented in our recent publication available at  (https://www.researchsquare.com/article/rs-34021/v1) In the much-watched Star Trek program, the dastardly Klingons would cloak their ships so that they were invisible to the USS Enterprise. In the human body, pathogens also cloak themselves to be invisible, seem like sugar or a food, by using sialic acids. Sialic acids are common on the cells of vertebrates and are the highest concentration in the brain. The immune system will not attack pathogens with sialic acid attached because they appear as a natural part of the human system. Dr. P. R. Raghavan has found that Metadichol, by expressing the CD33 gene, allows binding of these acids so that the immune system can disrupt the pathogen.  There have been many papers published on human healing by Dr. Raghavan that include an increase in stem cells, reduction of diabetes, and general well being realized with the use of Metadichol. The finding of the binding of sialic acid with the expression of CD33 and the increase in stem cells explains the healing of wounds quickly when using Metadichol. Below is a recently published paper by Dr. Raghavan on this topic.
    Metadichol acts to upregulate or down regulate CD33 depending on signaling mechanisms in human physiology.  Patents for Nano Soma were processed in weeks that often take 9 months.Read the many frontier health milestone science reports and anecdotal on www.thenanosoma.com site.

15. The Perspective on Bio-Nano Interface Technology for Covid-19

    GRAPHICAL ABSTRACT

    

    Graphical Abstract. Bio-Nano Interface Technology for Covid-19.

    Introduction

    Bio-Nano Interface deals with the convergence between the subcellular biomolecular machinery operating at the nanoscale and their interaction with nanoscale materials. The exploitation of this fundamental interface interaction leads to the emergence of a highly important area of research coined as “Nanobiotechnology.” The research on interfaces under the area of “Nanobiotechnology,” helps in understanding the fundamental biomolecular machinery and its dimensions at the nanoscale. Also, it leads to the attempts of artificial mimicking to invoke specific biological responses at the gene level. The possible interactions with nanoscale materials emerge either from man-made stimuli or through natural stimulations such as the physiochemical environmental interactions (volcanic eruption, cosmic dust, etc.,) with/without the involvement of biological systems (i.e., Carbon quantum dot presents naturally in honey, etc.) were explored. Hence, the interfacing of biological molecules using the principles and techniques in nanotechnology will aid in the understanding, development and improvement of the advanced biotechnological process essential for the product development. Implantable medical devices, nano-robots are one among the few examples of devices developed using the interface science.

    Biomolecules operating at the nano level are intelligent nanomachines capable of storing the genetic information and controlling the complex biological macrosystems. The role of biomolecules in combating the diseases can be traced back to the sixth century. The deadliest plague of Justinian in the sixth century eradicated half of the global population at that time. Later on, in the fourteenth century, high mortality due to the black death was reported. In 1918 influenza pandemic infected one in every three people on the global population (Wagner et al., 2014; Rai et al., 2020). From the history of infectious diseases (might be a selective pressure), it is learned that the human race is continuously surviving with the herd immunity as a result of natural selection. By the conceptual natural evolution, the ssRNA of virus interacts with the DNA of Human species and leads to the outbreak of a pandemic disease designated as Covid-19 (SARS-CoV-2). Possibly this might be due to the selective pressure to choose the suitable progeny for the next generation. Subsequently, the interaction of engineered nanomaterials with biological functional materials at the nanoscale opens an avenue for efficient prevention, diagnostics, and treatment that can provokes the combat against the virus. Herein, the exploration of the aspects of interfacial Bio-nanotechnology would give an insight into the possible solutions for the pandemic of Covid-19.

    Life Cycle of COVID-19

    In the first phase, the Covid-19 Spike protein (S1 subunits contain receptor-binding domain (RBD) and S2 subunits) binds with the host cell peptidase domain (PD) of the angiotensin-converting enzyme 2 (ACE2) (Nalawansha and Samarasinghe, 2020). At the same time, S2 subunits cleavage sites are sliced by host serine protease TMPRSS2, and as a result, it leads to membrane fusion and initiates viral entry. Hence, TMPRSS2 and RBD, the interaction sites of Covid-19 are considered as the target for clinical cure by blocking the entry and designing the inhibitor for treatment. The proteolytic cleavage of Covid-19 envelope releases the genomic RNA (Plus strand RNA) in the host cytoplasm. In the next stage, the virion mRNA (Negative strand RNA) exploits the host machinery (transcription, translation, endoplasmic reticulum (ER), and Golgi apparatus), to produce the necessary proteins such as S, E, and M proteins via translation process. Finally, the budding assembly holds the functional proteins and genome RNA and completes the formation of Covid-19 (Zhang and Liu, 2020). The newly synthesized Covid-19 viral particles have to be translocated by vesicles and must be released through exocytosis. This valuable information regarding the invasion, cell multiplication and the life cycle of Covid-19 will aid researchers to design the new therapeutic strategies and repurpose the existing drugs that counteract Covid-19 (Chauhan G. et al., 2020) (Figure 1). From the chemo-proteomic Covid-19 studies, 26 proteins are cloned, tagged and expressed in Human Cells (Skariyachan et al., 2019). As a result of affinity-purification mass spectrometry, 332 protein-proteins interactions are found between human proteins and Covid-19 that are physically associated with each of Covid-19. And the results helped in the identification of 69 lead compounds for host factors/human proteins as a target (Zeng et al., 2020). At the same time, the US Food and Drug Administration has approved 29 drugs, 12 clinical trials, and 28 preclinical compounds (Gordon et al., 2020). In addition to that, multiple ongoing viral assays studies reveal the inhibitors of mRNA translation and regulators of sigma-1 & 2 receptors as the two sets of pharmacological agents that exhibited antiviral activity.

    FIGURE 1

    

    Figure 1. The life cycle of Covid-19, (1) host cell recognition, binding, fusion and endocytosis (2) viral RNA genome is released into the cytoplasm (de Queiroz et al., 2020) (3) uncoating of the RNA and replication (4) translation into two replicate polyproteins (5) translocation of virion assemble and Golgi as vesicles (6) translocation to host cell membrane (7) exocytosis and their possible nanocarrier systems to target Covid-19.

    When Covid-19 transmits into the host, the median incubation period is ~5 days (Lauer et al., 2020; Omolo et al., 2020) and the active virus replicates in the tissues of the upper respiratory tract. Pharyngeal virus shedding will be very high during the first week of infections having 7.11 × 10⁸ RNA copies per throat swab on day 4 (Wölfel et al., 2020) and after 7 days, seroconversion occurs in 50% of patients. The presence of viral replicative RNA intermediates in the throat samples, preferably by analyzing throat swab and serological samples for the identification of Covid-19 infections. The presence of viral replicative RNA intermediates in the throat samples, preferably by analyzing throat swab and serological samples for the identification of Covid-19 infections. The fatality rate of COVID-19 is substantially lower, when compared to the earlier reported Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Whereas, being more transmissible, the virus has spread to over 213 countries so far, infected more than 9,050,000 people and claimed over 470,000 lives to date (Worldometer, June 22, 2020)¹. In the case of Covid-19, the particle diameter is around 50–200 nm (Chen N. et al., 2020) and It can be transmitted through human respiratory bioaerosols that could produce 3,000 droplets and possibly cause infections for 3 h both through airborne droplets and direct contact with infected persons. These bioaerosol droplets can spread from person to person if the people are <2 meters apart or touching surfaces upon which droplets have landed and that have not been disinfected. Recent studies demonstrated that the COVID-19 capable of surviving on plastic and stainless steel for up to 72 h, <4 h on copper and cardboard for <24 h (WHO).

    Inspiration From Virology in the Realm of Nanoscience and Nanotechnology

    The expansion of crystallographic studies toward biological samples like proteins and other complex organic materials got trigged in the early 1980s. Viruses have DNA or RNA as their functional genetic material and it is surrounded as well as protected by a protein coat (capsid). In some cases that the protein coat envelope is made of lipids. The wide spectrum architecture of the virus is icosahedral, and it possesses a surface antigen that restraints the geometric designs, insinuation for viral evolution, and has a binding affinity that exposes the pathological relevance. In the biological studies, two scientists contributed to the discovery of the first virus, Tobacco mosaic virus. In 1892, Ivanoski reported that the Chamberland filter-candle filtered leaf extract retains the potential infectious behavior. However, Ivanovski did not mention the virus. In 1898, Beijerinck was the first to term it as “virus,” after the incident of the tobacco mosaic. Inadequate but conclusive and complementary contributions to the discovery of viruses fetched by Ivanovski and Beijerinck (Lecoq, 2001). After the development of the first electron microscope by Max Knoll and Ersnt Ruska in 1931, it has been used to study bacteria at around 1938. And the electron microscopy has been used to elucidate the mouse Ectromelia virus, a member of the Poxviridae family. Further, the discovery of enzyme crystallization by J. B. Sumner (Nobel prize in 1946), lead to the structural elucidation of proteins (myoglobin protein, J. C. Kendrew and M. Perutz) and then the discovery of X-ray diffraction studies revealed the DNA structure (F. Crick, Jss. Watson and M. Wilkins) Later, in 1959 Richard Feynman had presented a lecture entitled “There’s Plenty of Room at the Bottom” in the annual meeting of the American Physical Society, at the California Institute of Technology (Caltech). This period accelerated the importance of material science and the search toward the nanoscale dimensions. Firstly in 1974, Norio Taniguchi used the word “Nano” meaning “dwarf” in Greece and thereby Taniguchi raised the term “Nanotechnology.” The first high 2.9 Å resolution of Tomato bushy stunt virus was elucidated by Harrison and colleagues in 1978 (Harrison et al., 1978). In 1981, Wilson et al. first elucidated the surface antigen of an influenza virus and this human viral pathogen exposed two glycoproteins (haemagglutinin and neuraminidase) on its lipid membrane envelope. Haemagglutinin glycoprotein is a homotrimer that comprises two structurally distinct regions of a triple-stranded coiled-coil of α-helices and a globular region of antiparallel β-sheet (Wilson et al., 1981). These comprise the host cell surface receptor binding sites that facilitate the initial viral entry, and the variable antigenic determinants that could target and neutralize antibodies. This pioneering crystallography work firmly established the relevance to the viral structures with receptor binding for biomedical applications. The most significant technologic developments were carried out after the use of a scanning tunneling microscope by Binning and Rohrer in 1981. The technique triggered the interest toward visualization, measurement, and manipulation of materials at the nanometer scale, as well as to measure the various forces. With the aid of atomic force microscopy, the enzyme activity (Radmacher et al., 1994) and the RNA polymerase activity (Kasas et al., 1997) at the nanoscale domain could be observed directly. Eric Betzig, Stefan W. Hell and William E. Moerner in 2014, were awarded the Nobel prize for to overcome the limitation of optical microscope resolution enhancement (>0.2 micrometers). Recent advanced frontier technologies such as Microarray, MiniION—nanopore sequencing device and DNA based computation are examples of the synergic combination of materials science with the functional biomolecules. The techniques help in analyzing the functional biomolecule expression of thousands of genes at the same time and were portable to high-throughput benchtop devices for the rapid, accurate and reduced sample processing time. The new techniques with advanced technology could store larger data in memory and conduct multiple operations at once, thus solving decomposable problems much faster than conventional computers. The progress in material science and its contribution to Bio-Nano advancements is summarized in Figure 2. Since the identification of the first virus, the coherence of advanced material science toward nanoscale has contributed to every aspect of understanding the virus from their basic structure, characteristics (i.e., mode of action) and functions at a molecular level. Recently, the structure of the S-proteins of Covid-19 was revealed using cryogenic electron microscopy (Wrapp et al., 2020). To understand the structure, 3207 micrographs were taken and combined into a 3D reconstructed model with a resolution of 0.35 nm (Le Ferrand, 2020). The obtained structural information paves the way to progress the antiviral drug development. A research team led by Tiangang Liu (Wuhan University) and Yan Li (Renmin Hospital) developed a nanopore target sequencing (NTS) method for rapid identification of COVID-19 along with other respiratory viruses concurrently. As one of the prominent field of the past decade, bio-nano interface technology admits prodigious potential contributes innovative solutions to the prevention, diagnosis, and treatment of COVID-19.

    FIGURE 2

    

    Figure 2. Timeline of progress made in material science toward the contribution of Bio-Nano advancements.

    Bio-Nano Interface Technology Toward COVID-19

    The term “interface” refers to a point where two systems, subjects, organizations, etc. meet and interact. In case of the bio-nano interface, the biological machinery is known to distinguish between natural structures differing from one another at the nanoscale based on a specific functional response. Nano dimensional materials inherits exceptional properties like mechanical, electrical, magnetic, optical, and various chemical and functional properties including the increase in the surface-to-volume ratio of the materials. When bio and nanosystems interact with each other, they could invoke a specific biological functional response and identify the target pathological conditions both at in vitro and in vivo. The physical meaning of the interaction between bio-nano systems is also influenced by the surrounding medium that could interfere and triggers the conformation, chemisorption, physisorption process along with the nanodimentional materials surface properties (Figure 3) (Lynch et al., 2015). Further, this leads to the mechanisms of specificity, cellular uptake, intracellular trafficking as the results provoke the functional response (Nel et al., 2009). Consequences of this effect could act as a key component to interface between the functional biological molecules of virus and human systems and as an advent to the understanding, development and improvement of an astonishing number of novel techniques and tools enabling the solution to Covid-19. Figure 4 shows the information about the patent registration office filing status related to Covid-19, as on July, 18 2020, from Nano-Nature database. This infers the technological insight into the Covid-19 (Gupta and Gupta, 2020). Here, we discuss the recent progress under the commercial product development stage in the field of nanoscale engineering that operates with a bio-nano interface and could potentially be employed to address significant challenges in prevention, detection and treatment of Covid-19.

    FIGURE 3

    

    Figure 3. Illustration of the bio-nano interface technology.

    FIGURE 4

    

    Figure 4. Patent registration office filing status of “Covid-19” from Nano-Nature database (as on 18/07/2020).

    Prevention

    The priority of the defense is to prevent and control the infectious respiratory disease of COVID-19, the first line of defense should be preventing exposures through the implementation of control measures such as isolation, quarantine, restriction or closure of gatherings, and/or the use of ventilation by proper local extraction. Also, during the outbreak of the pandemic, it might be useful to practice effective measures, such as respiratory hygiene/cough etiquette and hand washing. The detailed information of Covid-19 transmission is yet to come, but the droplets of around 5 μm released from coughing or sneezing are considered as the primary source of respiratory infection (van Doremalen et al., 2020; Wang and Du, 2020). Further, it is reported that the droplets smaller than 1 μm persist for longer durations up to 8 h (Morawska, 2006; Konda et al., 2020) in the environment. Covid-19 aerosol droplets have shown to remain suspended in the air for ~3 h (Huang et al., 2020; van Doremalen et al., 2020).

    Self-Disinfecting Surfaces

    Protecting the front line healthcare workers from Covid-19 is of prime importance to continue fighting the pandemic. Hence, enabling nanotechnology in the personal protective equipment (PPE) may introduce additional features like hydrophobicity and antimicrobial activity without altering the characteristics of the original texture of the material, breathability, durability and comfort. An example is the use of nanowhiskers in the textiles that provides hydrophobicity employing 3 fold smaller than cotton fiber and hence results in an increase of surface tension that prevents the water droplets. Also, antimicrobial activity on the different surface materials can be achieved by different coating methods using nano dimensional materials like metal NPs (zinc oxide, tin oxide nanowires, titanium dioxide, Au, Ag and Silicon), natural bioactive polymer and chemically functionalized polymers that can inhibit the growth of the microbes. These agents with specific target might intervene in the synthesis of viral RNA replication and inhibit the viral assembly. Weng et al. (2012), reported a self-disinfecting surface by depositing the nanocrystals of CuInZn₄S₆ (CIZS). The nanocrystals could get activated by absorbing visible light and liberate active oxidative species (H^., OH^.,

    CO2._

    , ¹O₂,) which are responsible for the oxidation of the amino acid residues present in the protein envelope of the viruses. And the reported works encourages further research on the disinfection of virus through the inactivation of their protein envelopes.

    Respiratory Masks

    Effective use of surgical masks and N95 respirators among healthcare workers prevents influenza-like infections (Long et al., 2020; Samrat et al., 2020) and SARS (Seto et al., 2003). Hence masks play a vital in preventing the Covid-19 progression. On the other hand, the global shortage of surgical masks and N95 respirators is a major concern (Esposito et al., 2020). In line with the US (Centers for Disease Control Prevention, 2019) (CDC), healthy people are recommended to wear a cloth face mask in public (CDC)². A report by Konda et al. (2020), summarized that cotton, natural silk, and chiffon exhibited better protection against the infection, generally above 50% in the entire 10 nm to 6.0 μm range furnished the tight weave (Konda et al., 2020). Further, they have also concluded that the higher threads per inch of cotton with tighter weaves resulted in effective filtration (for aerosol-based virus transmission) efficiencies. The use of cloth masks, in general, has several advantages such as cost-effectiveness, sustainable re-use and convenience for the common people. In addition to that, it will also reduce the usage of disposable surgical masks and N95 respirators by the general population, so that it can be reserved for the frontline workers. In this perspective, our team has come up with the idea of sustainable development of a plant extract (comprising antiviral compounds) along with graphene to produce a bio-nano composite solution to modify the commercial cloth materials, surgical mask and air filters as shown in Figure 5. Interestingly, graphene with its nano dimension (atomic thickness 0.335 nm) could trap the virus-like particles and along with the impeded antiviral compounds from plant extract, it could be able to inactivate the virus particles. Further, our method is cost-effective and scaled to the industrial process, realizing the technology readiness level (TRL) of 3. More importantly, the aim of our method is to simplify and make it adaptable to prepare in home by utilizing the available materials such as graphite pencil, ginger, aloe vera and commercial mixer (Under the submission of IMPI-México).

    FIGURE 5

    

    Figure 5. Proposed surgical mask or air filter along with graphene-based bio nanocomposite.

    The proposed material made of the nanofiber membranes is attractive due to the dense nanofiber network, high surface area, biodegradability, extended durability, and re-usability. One such highly breathable, disposable, and biodegradable filter cartridge of cellulose nanofiber-based material was tested by Queensland University of technology to remove the virus size nanoparticles. Polyacrylonitrile nanofibers respiratory masks are also produced by the OxinSabzEspadan, Nano Tar Pak, Nano FanavaranKhavar, and ModiranToseeSalamat Iranian. The reusable nano-filtered face mask developed by KAIST which is washable more than 20 times has shown bactericidal properties. Likewise aligned nanofibers in orthogonal or unidirectional direction with a diameter of 100 ~ 500 nm design has a patented technology. Now, this product is awaiting the final approval from the Ministry of Food and Drug Safety. An exclusive nano-coco-carbon™ filter from the Metamasks products made of coconut shell carbon and nanofiber matrix is invented. It allows <1 mm particle and prevents toxic airborne pollution. Another innovative nanocomposite of PLACTIVE^®and MDflex^® from Copper3D face mask has an active three-layer filtration system of non-woven polypropylene impregnated with 5% copper oxide nanoparticles, to explore the antiviral and antibacterial activity. Silver nanoparticles functionalized graphene oxide ink synthesized by ZEN Graphene solutions Ltd, collaborated with Graphen Composites Ltd, and documented to eradicate earlier versions of coronavirus. This graphene-based composite virucidal ink could improve the protection efficiency when applied to fabrics, masks, and other personal protective equipment. Three-layer nanofiber membrane incorporated with copper oxide (CuO) nanoparticles also significantly improved the filtration efficiency (99.9%) and virucidal activity produced by the RESPILON’s ReSpimask^® VK. Currently, this product complies with the requirements for medical equipment of type IIR of standard EN 14683. Self-regenerating germicidal TiO₂Ag nano facemask was developed by X.TiO₂ Inc. They proposed that the outer TiO₂ layer, when exposed to direct sunlight (UV), eradicates the accumulated germs. Also, it has a greater odor-absorption capacity and regeneration capacity by light. The same group has introduced multi-tier mask made of titanium dioxide-silver nanoparticles that can be able to destroy over 650 germs under without light conditions.

    Vaccine

    Development of a vaccine is a laborious time consuming and expensive process. Indeed, it has less probability of success and selects the better candidate from the several candidates, further it takes a long period to have a licensed vaccine (Gouglas et al., 2018). The formulations of vaccines entailed of attenuated viruses (non-virulent strain), destroyed pathogens (inactivated) or subunit of protein antigens can elicit a specific immune response (Figure 4). The efficient vaccines such as Influvac R (Daubeney et al., 1997), Vaxigrip R (Delore et al., 2006), and Fluzone R (Grohskopf et al., 2015) are used against influenza type A and type B virus which has been developed by the inactivated/fragmented trivalent or quadrivalent. Moreover, the introduction of the nasal administration of live attenuated vaccines like Nasovac R and Flumist R in young children (Carter and Curran, 2011; Dhere et al., 2011) is already in the process. Vaccines using live-attenuated viruses against influenza are shown to be risky in elderly and immune-suppressed humans (Chattopadhyay et al., 2017). However, either the use of the destroyed pathogen vaccines or virus-derived subunit vaccines induce a lower immune response, and often an adjuvant is required to boost the efficiency (Vartak and Sucheck, 2016). New vaccine modalities like the subunit vaccines (Norton et al., 2012), and antigenic proteins in pathogens that encode DNA vaccines (Luke et al., 2011) are being exploited. Interestingly, though these two new vaccines exhibit a higher safety profile, it lacks relatively lower immunogenicity. In general, researchers characteristically follow a linear sequence of steps with multiple checkpoints for data analysis or manufacturing process. But Covid-19 crisis demands an urgent need for developing a vaccine at a faster rate that requires a new pandemic paradigm of the evaluation process.A quick start and multiple steps should be executed in parallel before confirming a positive outcome of an adjacent step (Lurie et al., 2020). The exploitation of reverse genetics and next-generation sequencing technologies could be shortening the time for the development of more conventional vaccine at this pandemic. However, the development of Covid-19 vaccine has its obstacles. (1) Spike protein antigen design is critical to ensure optimal immunogen response. The most prevalent form of Covid-19 variant in the global pandemic has to carry the spike protein amino acid change at D614G (Korber et al., 2020). Additionally, there is a dispute for the best immunogen approach as to whether to target the complete protein chain or only the receptor-binding domain. (2) The exacerbating side effect of lung disease noted either directly or as a result of antibody-dependent enhancement, in the case of SARS and the Middle East respiratory syndrome (MERS). Hence, it should be concerned about the selection of a suitable animal model and laborious safety monitoring in clinical trials. (3) There is no clear evidence of protection that correlates from SARS and MERS vaccines. Further, the potential duration of immunity is unknown as with naturally acquired infection, and hence there is uncertainty in the dosage of the vaccines (Lurie et al., 2020). (4) The most important challenges of the vaccine are to stimulate both the T cell and B cell immunity against Covid-19 (Chauhan D. S. et al., 2020). (5) From the genome-wide association study on Covid-19 it reveals that the genetic variations might be associated with the severity of infection (Aiewsakun et al., 2020). Many mutations and deletions on coding and non-coding regions are also observed (Phan, 2020). Nevertheless, the high level of genetic mutations (antigenic drift) of viruses should be considered because it might have a chance to reduce the efficacy of the vaccines (Boni, 2008; Graham and Anderson, 2013). An alternative approach to the conventional vaccines is to present the relevant antigenic moieties at the particle of nanoplatforms. At present, there is a wide variety of the nanoparticles evaluated as antigen carriers, with inorganic, polymeric nanoparticles, virus-like particles (VLPs), liposomes and self-assembled protein nanoparticles (Figure 6). The main advantages of these materials are their nano dimensions as they pave the easier interaction with the biological functional molecules (DNA, RNA and proteins) at the nanoscale (Laval et al., 2000). Further, it can be administrated via subcutaneous and intramuscular injections or delivered through oral, intranasal (mucosal sites) and also through penetrating capillaries as well as mucosal surfaces (Parveen et al., 2016; Schneider et al., 2017; Smith et al., 2017). Recent signs of progress in the material science can control and tune the size, shape, solubility, surface functionalization and hydrophilicity that could allow the synthesis of nanoparticles with tailored biological properties (Angioletti-Uberti, 2017; Al-Halifa et al., 2019). Besides this, the incorporation of a wide range of antigenic molecules into the nano dimensional particles makes notable modulations of immunogenicity (Irvine et al., 2015; Szeto and Lavik, 2016). Most importantly, the available nanotechnology tools and techniques are used for the design of vaccine carriers with special focus on effectiveness, immunogenicity modulation and biosafety to tackle the current outbreak. Various institutions and bio firms have kick-started the vaccine development as soon as the first genetic information was posted. The genetic information would give us the significant genomic match of Covid-19 with the previous coronavirus and will help in elucidating the potential vaccine candidates. To get preferable vaccine target candidate nAbs are induced against S protein of Covid-19, and the ACE2- mediated host uptake must be prevented. In the circumstance of SARS/MERS, vaccine development research puts forward RBD of the S1 subunit and functional information (protein/gene) of S could act as preferred target sites (Chen W.-H. et al., 2020; Prompetchara et al., 2020; Verma et al., 2020; Zhang L. et al., 2020). Available specific antigens information on Covid-19 is limited that could obstacle the trial vaccine candidates. Covid-19 nano vaccine candidate scheme depends on (1) Antigen-Dependent Nanocarrier Selection and (2) Vaccine Adjuvant Nanoparticles.

    FIGURE 6

    

    Figure 6. Nanocarrier system for the effective vaccines and treatment for possible use in Covid-19.

    (1) Antigen-Dependent Nanocarrier selection:

    Factors such as the physicochemical characteristics, biological stability, target sites, and controlled immunomodulatory release of antigens decide the presence of antigens either inside or on the surface of the nanocarriers. The interaction of antigen on the surface of nanocarrier is based on physical adsorption of surface charge and through non-covalent hydrophobic interaction. The amphoteric nature of the antigen facilitates the adsorption or surface immobilization of antigens on nanocarriers such as chitosan, dextran sulfate-based polymeric nanoparticles, inorganic nanoparticles, and carbon nanotubes (Zhao et al., 2014; Irvine et al., 2015; Salazar-Gonzlez et al., 2015; Pati et al., 2018). The mRNA and DNA based vaccines are straggled by the degradation of extracellular RNase and nucleases, hence the delivery vehicle is vital in both cases (Geall et al., 2012; Lung P. et al., 2020). These mRNAs are entailed cell-specific receptor recognition and cross the lipid membrane. The cytosolic presence of exogenous mRNA is initiated to trigger the synthesis of functional protein (Reichmuth et al., 2016). The self-assembly of an ionizable cationic lipid resulted in lipid nanoparticles (LNPs) of size 80–200 nm (Kranz et al., 2016). It has the ability to deliver mRNA on specific target site effectively. The sustained release provokes the opting for intramuscular and intradermal routes, resulted in high antibody, B and T cells immune response (Kanasty et al., 2013). Lipid nanoparticles (LNPs) is employed as an encapsulated carrier for the mRNA-1273 that encodes for a full-length, prefusion stabilized spike (S) protein of Covid-19, under the clinical trial (NCT04405076-Phase 2 and NCT04283461-Phase 1) performed by the Moderna (Figure 6). Once the availability of the genetic sequence information, within a short period developed the mRNA based Covid-19 vaccine candidate by Moderna’s that entered phase 1 clinical trial on March 16, 2020. LNPs-mRNAs vaccine is an ongoing clinical trial of phase 1/2 (2020-001038-36 and NCT04368728) that uses the four prophylactic SARS-CoV-2-RNA against Covid-19. The clinical trial of phase 1, ISRCTN17072692 used LNP-nCoVsaRNA that is encoded with the Covid-19 spike protein. The physical technologies of gene gun and electroporation also play a vital role to improve the delivery of the mRNA/DNA across the cell and nucleus membrane. Prominent elicitation of B and T cell response found in pig is based on surface electroporation of DNA coated-PLGA nanoparticles (Hutnick et al., 2012). This portable electroporation technology is now exploited as an ongoing clinical trial to insert a DNA plasmid that encodes the S-protein of Covid-19 (NCT04336410 and NCT04447781).

    (2) Vaccine Adjuvant Nanoparticles (VANs):

    The intrinsic adjuvanticity of the nanoparticles is capable of activating the complement system, inducing the autophagy and the activation of inflammasome (Hamad et al., 2010; Chauhan G. et al., 2020). Curiously the surface functional group and hydrophobicity of nanoparticles, along with other physiochemical properties, are capable of inducing the adjuvanticity mechanisms (Thomas et al., 2011) (Figure 6). As a result, VANs are conceived as amend for the efficacy and safety of the immune response. Notably, the vaccine adjuvants are capable of reducing the required dosage of antigen, and it results in making it available to a larger population (Reed et al., 2009) at this pandemic situation.

    The full-length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine is adjuvant with Matrix under the clinical evaluation of Phase 1/2NCT04368988) (Baviskar et al., 2020). Further, Adjuvanted recombinant protein (RBD-Dimer)NCT04445194 and recombinant spike protein with Advax™ adjuvant of NCT04453852 is under the phase 1 clinical evaluation (Table 1) (Samrat et al., 2020). Among the other COVID-19 preclinical vaccine candidates, five of the protein subunit vaccine candidates reported a combination of antigen and adjuvant. A recombinant Covid-19 glycoprotein with a matrix M (an adjuvant) used in the NVX-CoV2373 nanoparticle vaccine is expected to move into clinical trials shortly. Recently, AS03 (GlaxoSmith-Kine), MF59 (Seqirus), and CpG 1018 (Dynavax) are the licensed adjuvants developed specifically for preparing Covid-19 vaccine.

    TABLE 1

    

    Table 1. List of vaccine candidates under the clinical evaluation (DRAFT Landscape of COVID-19 candidate vaccines– as of July 2, 2020, by WHO).

    A remarkable number of nanotechnological pre-products are used in the ongoing vaccine clinical evaluation and preclinical stage as per the list from the DRAFT Landscape of COVID-19 Candidate Vaccines (as of July 2, 2020, by WHO) (Table 1). The nano dimensional materials effectively cross the cellular membrane barriers and reach its specific target site. On reaching the targeted site, it facilitates the controlled release, and stimulate the immunomodulatory activity to induce the desirable defense mechanisms (i.e., target both adaptive–T cell and B cells and innate immune systems of macrophages, monocytes, neutrophils) inside the host (Chauhan G. et al., 2020). As a result, there is eminent efficacy and safety in disease control. Further in the development of vaccine process, intrinsic adjuvant property in few nanomaterials and effective delivery of adjuvants resulted in reducing the dose-sparing which could reduce the production units and made it accessible to the larger demand at the pandemic situation. In conclusion, nanotechnology explicit its major role in the futuristic lead vaccine development.

    Immunomodulation Aspect in the Context of Nanomaterial-Based Vaccine Development

    Under the severe conditions, Covid-19 patients suffer from major invasion and damage impact on lung and the juxtaposed endothelial tissue by innate immune phagocytes (neutrophils and macrophages) (Pisani et al., 2020). To overcome this critical issue, it is recommended to use anti-IL-6 antibody tocilizumab and Siltuximab in the clinical trials. Nevertheless, care should be taken for the effective control and suppression of innate immunity associated with cytokine production (Pisani et al., 2020). Nano based systems plausibly counteract these critical issues and might have the potential to improve the specificity and controlled immunosuppressant delivery. And it could be attained by fine-tuning the surface charges of the nanocarrier systems. The surface charges could improve encapsulation with the required loading of the anti-immunosuppression drugs, pertinent to reduce drug dose as well as the non-target drug distribution, and possibly undesirable consequences.

    Further, it can deliver targeting specific immune subpopulations to avoid the provocation of other immunological responses. Experimental results of the Octadecylamine functionalized nanodiamond with dexamethasone demonstrate the anti-inflammatory and pro-regenerative activity in human macrophages under in vitro. Additional, it also has reduced the macrophage infiltration and controlled expression of iNOS and tumor necrosis factor (TNF)-α (proinflammatory mediators) (Weiss et al., 2020). The occurrence of the ordered structure, controlled porosity with surface charges on the nano dimensional carbon materials has exhibited the effective adsorption of IL-6 and TNF-α (Weiss et al., 2020).

    Diagnosis

    One of the urgent needs in the Covid-19 pandemic is a multiple diagnosis test; this infers to take the strategical decision depending on the population density of all over the major cities in the world. The substantial concern in the diagnosis is sensitivity, specificity and accuracy, which further leads to the rapid implementation of proper containment of Covid-19 (i.e., identification, isolation, contact tracing, and treatment) that limit the spread.

    Molecular techniques are vital in diagnoses as it shows the higher target and specificity of pathogens. For the development of molecular techniques, first, we should understand the composition of the functional biomolecules (proteomic and genomic) of the pathogen, its entry into the host system and associated induction response by expression in the functional biomolecules. There are two main class of functional biomolecules where diagnosis are performed: (1) in nucleic acids (RNA-DNA) and (2) in proteins (Serological test-Induction response of viral antigen and antibodies). The priority is given to the nucleic acid-based methods by the WHO. This method is focused on direct amplification of the virus genetic material from the patient sample that offers high sensitivity (85–90%) and specificity with the aid of polymerase chain reaction (PCR) under the thermal cycler. Two strategies are used in a PCR test, (a) Reverse Transcriptase-PCR (quantitative) (b) Loop-Mediated Isothermal Amplification- PCR (LAMP-PCR) (qualitative) (Arun Krishnan et al., 2020). The RT-PCR method involves the reverse transcription of Covid-19 RNA into cDNA (Complementary DNA) strands, later by amplification of the specific gene of interest in the cDNA (Kageyama et al., 2003). This method targets the three genes of interest to detect viruses from the beta-coronavirus group (E gene- codes for envelope protein), N gene code for nucleocapsid protein and RdRP gene code RNA dependent RNA polymerase in the open reading frame ORF1. More specifically, the RdRP and E genes have high sensitivity toward Covid-19 with a technical limit of detection of 3.6 and 3.9 copies per reaction (Udugama et al., 2020). According to the WHO’s recommendations, the RT-PCR test must detect three genes in a single reaction mix. This would sort out the false-positive results and guarantees double confirmation (WHO Diagnostic Detection of RT-PCT report)³. The upper respiratory (nasopharyngeal swabs, oropharyngeal swabs, nasopharyngeal washes, and nasal aspirates) samples and lower respiratory tract (sputum, BAL fluid, and tracheal aspirates) samples are used for diagnosing Covid-19. From the above, the broadly recommended sampling method is the upper respiratory sample collection (Interim Guidelines). In the RT-LAMP involves in the conversion of RNA to DNA followed by amplification of sample genome using forward inner primer and outer primer; reverse inner and reverse outer primer that targeting different regions of the DNA (Notomiet al., 2000). As a result, a higher specificity with the detection limit of ~75 copies per μL will be obtained. This method is easy to operate with a low background signal and can be visualized by a color change either by the use of pH-sensitive dye or fluorescent dye that binds to double-stranded DNA (Notomi et al., 2000; Mori et al., 2001). CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats) system have been proposed for the rapid detection of Covid-19. CRISPR is a set of DNA sequences, that results from an adaptive immune system in prokaryotic organisms (archaea and bacteria) against the previous infection of phages. Under this Cas, protein has different utilities in gene editing (Cas9) and diagnosis (Cas12a and Cas13a). Recently, CRISPR/Cas13 system has been exploited for the detection of Covid 19 in SHERLOCK [specific high sensitivity enzymatic reporter unlocking (Kilic et al., 2020)] technology by Broughton et al. (2020). In the coronavirus genome, Cas13 is targeted to the S and ORF1ab protein genes, where it binds and initiates the random cleavage of ssRNA. With the aid of a fluorescent probe as a transducer in this technology, it makes the possible way to quantifiable as well as visible confirmation of positive case (Metsky et al., 2020). Thiol functionalized Gold NPs with N-gene (nucleocapsid phosphoprotein) oligonucleotides are capable of diagnosing Covid-19 from the RNA isolated samples using colourimetric assay within 10 min. This rapid diagnosis kit progresses in the identification of infection on time, though the viral loading in the infected sample might obstruct the diagnosis. To resolve the above-mentioned issues, two-dimensional gold nanoislands are functionalized with the complementary oligonucleotide sequence of elected Covid19 gene sequence (RdRp-COVID, ORF1ab-COVID, and E genes from SARS-Cov-2) (Parihar et al., 2020; Srivastava et al., 2021). During the nucleic acid hybridization with the infected sample, two different angles of incidence at their plasmonic photothermal (PPT) and localized surface plasmon resonance (LSPR) exhibited the two different excited wavelengths (Xu et al., 2020). This unique combination feature of surface PPT and LSPR effects results in higher sensitivity (< concentration of 0.22 pM), stability and reliability in the Covid19 sensing (Talebian et al., 2020). Yet another combination of two technologies such as reverse transcription enzymatic recombinase amplification (RT-ERA) and fluorescence resonance energy transfer (FRET) was exploited in Exo FRET method with the ultrasensitive detection (0.32 × 10⁻¹⁸M) of Covid-19. FAM and BHQ1 were used as quenching probes and located close together along with the THF site. An exonuclease II can recognize the THF site and proceed to cleave the double-strand nature of the RNA sense sample with amplicon. As a consequence of this, the cleaved strand leaves the BHQ1 probe and restores the FAM fluorescence probe and later it helps in quantifying the FAM probe and achieve the ultrasensitive detection (Yang et al., 2020). (2) Proteins (Serological test-Induction response of viral antigen and antibodies)- The protein constitution of antigens and antibodies exploited in the serological assays can find/measure antibody response due to induction response of pathogens (Covid-19) in body fluids (blood serum or plasma). This involves the use of the different platform, including binding affinity assay (enzyme-linked immunosorbent assays-ELISAs, lateral flow assays or western blot-based assays) and functional assays such as virus neutralization, enzyme inhibition or bactericidal assays. These essential tools are involved in the management of infectious diseases, including diagnosis of infection and treatment (seroprevalence assessments and antibody titers upon vaccination) (Krammer and Simon, 2020). Once the human body encounters the Covid-19 infection, our body responds to produce IgM and IgG antibodies at the 7–10th day and 14–20th day, respectively. Even though the shorter detection of IgM can disappear earlier, however, IgG can persist over a long period after the infection. Besides antibody detection, spike glycoprotein and nucleocapsid protein antigens are under development for the early stage detection of Covid-19. Point-of-care (PoC) testing devices are used for rapid diagnosis without sending samples to a centralized well-equipped laboratory and don’t require professional experts to analyze the samples experiment. This portable molecular device would significantly contribute toward cost-effective, robust and simplicity of inference results. Most widely, PoC uses one of the serological assay called as lateral flow immunoassay. This method adopted to detect Covid-19 biomarkers, IgG and IgM with impeded gold nanoparticles conjugates in the test strip. Once the patient’s sample is placed on the nitrocellulose membrane strip, with the aid of capillary force the protein is drawn across the strip. The biomarkers reached with the corresponding antibodies, reveals the visible color change as a line (Figure 7). A field-effect transistor with graphene sheet coating surface functionalized with the spike protein antibody act against Covid19, and it can show the higher sensitivity against Covid-19 even with the presence of Middle East respiratory syndrome coronavirus (MERS-CoV).

    FIGURE 7

    

    Figure 7. Serological diagnostic kit for Covid-19 utilizing the gold NPs.

    The IgM and IgG in the lateral flow assay have demonstrated a clinical sensitivity (57 and 81%), specificity (100 and 100%), and accuracy (69 and 86%) (Udugama et al., 2020). Clinical sensitivity of 82% realized in a test detects both IgM and IgG (Xiang et al., 2020) antibodies. Recently, Sona Nanotech, Mologic, and SureScreen Diagnostics are developed a quick response lateral-flow test to identify the COVID-19 within 5–15 min. Enzyme-Linked Immunosorbent Assay (ELISA) and Chemiluminescence Immunoassay (CLIA) are quantitative serological techniques to detect specific antigen or antibody. The ELISA test is developed to detect Covid-19 IgM and IgG antibodies by Zhang W. et al. (2020). Anti-IgG antibody conjugated with horseradish peroxidase and SARS-CoV-2 Rp3 nucleocapsid protein is adsorbed on the 96 well plate surface as biomarkers (Zhang W. et al., 2020). The manufactures of IBL international, DRG Diagnostics GmbH, Epitope and Euroimmun developed manual ELISA kits to detect the IgG and IgM antibodies (Mungroo et al., 2020). Serological detection kits are under development by the manufacturers in the worldwide. However, the major concern should be taken care of false-positive results that might be evidenced by previous virus infections other than Covid-19, such as coronavirus HKU1, NL63, OC43, or 229E. Moreover, detection limit in the “window period” (i.e., the when specific antibodies are not yet detectable range in a patient’s sample) may exceed 7 days is deprived thus might prove negative results. Hence, serological tests can’t be used as a predominant basic diagnosing tool in Covid-19 (Lauer et al., 2020). Concerning the current indication, WHO recommends that the new PoC immunodiagnostic test proceeds in a research lab alone. Further, it should not consider for clinical decision making until the further confirmation supporting test result is available (WHO/2019-nCoV/Sci_Brief/POC_immunodiagnostics/2020.1–as of April 8, 2020). In contrast, serology tests could help healthcare professionals to identify the development of immune response, further determining to select the donors of convalescent plasma. This would serve for the seriously ill patient of Covid-19. After the vigor’s evaluation, The Food and Drug Administration (FDA)-Emergency Use Authorizations (EUA) authorized the serology test performance on their website (Supplementary Table 1)⁴. It should be noted that widespread testing is needed to keep the outbreaks of Covid-19 under control. Nevertheless, in many regions, there is a shortage of reagents needed to run tests and lack of infrastructure to proceed further. In that case, a serological based rapid test could be a better option.

    Treatment

    The fundamental studies of the Bio-Nano interactions could be revised to understand the Covid-19 infection with the human system (Chan, 2020). The coherence of material science advancements reveals the genetic information, protein structure modeling and mode of pathophysiology/immunogenicity. This information further leads to the identification of a target that would facilitate effective treatment. The possible target is the viral system—3CLpro, PLpro (viral protease) and S protein, host cell protease—transmembrane serine protease 2 (TMPRSS2) (Weiss et al., 2020), angiotensin-converting enzyme 2 (ACE2) and RNA-dependent RNA polymerase (RdRP). Based on the target sites as mentioned above, the finding of new small molecules is under development meanwhile there is search for the existing antiviral molecules (Gordon et al., 2020; Hoffmann et al., 2020; Lung J. et al., 2020; Zhang L. et al., 2020). Artificial intelligence also takes part in the identification of potential drug molecules for Covid-19 treatments (Tang et al., 2020; Zhou et al., 2020).

    Nanomedicine could open a possibility for the design of a new therapeutic agent and the treatment for Covid-19 (Figure 6). A nanomedicine approach is a powerful vital tool (Petros and DeSimone, 2010), which can have the ability to transform/deliver antiviral drugs effectively and improve Covid-19 therapeutic efficacy. Nano-carriers based therapeutics would tackle the current limitations (i.e., poor aqueous solubility and low bioavailability) of antiviral therapy and offers several opportunities to improve the efficacy (Figure 6). This has a capacity of crossing the biological barriers to attain therapeutic concentrations in protected viral reservoirs (Kobayashi et al., 2014) and reaches the specific target organ/intercellular sites involved in the Covid-19 pathophysiology such as ACE2 expressing cells, viral S protein domains, cathepsin binding sites, etc. Further, the sustainable drug-releasing nanocarriers can mitigate the risk effects of deprived patient compliance and the rebound of viral during the treatment for infections. Therefore, nanocarriers based antiviral drugs delivery system could be able to modify the antiviral drug pharmacokinetics/pharmacodynamics properties and the results are reflected in the reduction of drug dosage, reduced side effects, and improved bioavailability of drugs (Lembo et al., 2018).

    The respiratory disease of Covid-19 has affected lungs severely in the 14% of cases leading to lung swelling and fills it is with fluid and debris. Actively delivering a drug directly to the site may prove an effective treatment strategy. However, this task is limited by the complex mucus environment in the lungs. This problem could be overcome by the use of mucoadhesive particles (MAP) for pulmonary drug delivery. The core hydrophobic polymers have highly cationic or thiolated of decorated nanoparticles surface, which favors the interaction with negatively charged glycosylated or cysteine-rich hydrophobic domains of airway mucin fibers (Schneider et al., 2017). A consequence of this facilitates the long duration retention in the lungs by reducing the mucociliary clearance rates via rheological changes of mucus by multivalent mucus particle interactions (Schneider et al., 2017). Further, the MAP diameters (large as 200– <300 nm) smaller than mucus mesh spacings would have crossed the mucus layers easily. The repurposed Covid-19 drug composition effectively formulated with MAP system might be an effective target for the treatment.

    In addition to the conventional antibodies, a single variable domain antibody without an effector domain is coined as VHH or nanobody (Nb). Heavy-chain-only antibodies (HCAbs) produced by camelids have a single variable domain that acts as the target recognition module. Nbs possess various advantages over the conventional antibodies, that includes a structure-function concert at nanoscale dimensions leads to higher solubility and homogeneity, chemical and thermal stability, docility into multiple formats, facile penetration, and reach specific target site with antigenic affinity and specificity, inferior vulnerability to steric hindrances (Konwarh, 2020b). This attractive features of nanobodies are plausible combat against Covid19. At this junction, Martinez-Delgado (2020), reported that the nanobodies derived from camels, Nb11-59 unveiled promising therapeutic against Covid-19 with ND₅₀ of 0.55 μg/mL, exclusively via nebulization.

    Regarding Off-label use of medicines for the Covid-19, the scientific brief from the WHO (update March 31, 2020) (Adhikari et al., 2020), communicate that none of the specific pharmaceutical products has yet been shown to be safe and effective for the treatment of Covid-19. Despite the promising response of remdesivir in clinical trials, it could be considered for inhibition of viral replication for the treatment of Covid-19. Prominently, to replicate the Covid-19 genome takes more than a single polymerase and ensure the pathogenicity. There are nine structural and non-structural proteins (nsps) in the viral replication-transcription complex (RTC) that are involved in the cell multiplication of Covid-19 (Chan et al., 2020; Ortiz-Prado et al., 2020). Nevertheless, a good number of medicines have been suggested as potential investigational therapies. Most of the drugs in a combined form known for closely related therapeutics have shown better response, depending on the stage and condition of the patient. Apart from this new clinical trial, the Solidarity trial is co-sponsored by WHO along with participating countries.

    Solidarity trials interim results showed that the practice of the hydroxychloroquine and lopinavir/ritonavir not able to change the mortality of COVID-19 patients (“Solidarity” clinical trial for COVID-19 treatments-Latest update on treatment arms dated on July 6, 2020). Nanocarriers in the delivery of multiple drugs with diverge physicochemical properties are essentially beneficial for combination therapies (Destache et al., 2009; Shibata et al., 2013). The technological feasibility enables the fabrication of a variety of nanomaterials designed to carry the multiple drug carrier, which facilitates the sustainable control in synergistic drug compositions, improved pharmacokinetics, and reduced side effects. There have been a promising in vitro and in vivo studies of blood-brain barrier transmigration with significant anti-HIV activity evaluated in primary central nerves system cells using nanoformulation (pegylated-magneto-liposomal based nano delivery) with multidrug compounds load (antiretrovirals, latency reactivating agents, and drug abuse antagonist) (Jayant et al., 2018). To overcome the lymph node drug insufficiency, an oral combination of drugs has been formulated in a lipid nanoparticle-based delivery system accommodated with three antiretroviral drugs, lopinavir, ritonavir, and tenofovir (hydrophilic drug). The drugs have shown long-lasting plasma drug profiles and improved lymph node drug delivery levels evaluated in the macaques in vivo model (Kraft et al., 2018). These methods of multidrug based Nano delivery system could be adaptable to Covid-19. But various parameters such as analyzing the interaction between each drug compounds, controlling the release profile of each drug and balancing the antagonism/synergy/toxicity (Ma et al., 2013) should also be considered. The cholesterol modified hydroxychloroquine (CholHCQ) laden liposome can reduce the dose and toxicity of hydroxychloroquine. Further, it inhibited the proliferation of rat lung fibroblasts, and as a result, it exhibited reducing the pulmonary fibrosis (Liu et al., 2017; Chauhan G. et al., 2020). This strategy of control viral load and target site would be beneficial to the Covid-19 treatment. Hu et al. (2020) proposed a mechanism involving chloroquine-induced suppression of phosphatidylinositol binding clathrin assembly protein (PICALM), which prevents the endocytosis-mediated uptake of Covid-19 (Chauhan G. et al., 2020). The use of target-specific CRISPR-RNAs (crRNAs) can protect the host systems from the infection via CRISPR-Cas13 system (Konwarh, 2020a). This effective antiviral system specifies the target ssRNA to degrade and inhibit further proliferation of infection. In this sense, prophylactic antiviral CRISPR in the human host (PAC-MAN) approaches are to utilize Cas13d of RNA-guided RNA endonuclease activity in the host to target the Covid-19 (Nalawansha and Samarasinghe, 2020) and cleave the RNA sequences (Abbott et al., 2020). With the aid of effective nanocarrier with PAC-MAN directed toward lung epithelial cells would be repurposed treatment of Covid-19.

    In a cytokine storm, the outcomes are the Hyperinflammation and macrophage activation syndrome, uncontrolled production of IL-1β, IL-6, and TNF-α (knows as proinflammatory cytokines). Under severe conditions, Covid-19 patients have the major invade and damage impact on lung and the juxtaposed endothelial tissue by innate immune phagocytes (neutrophils and macrophages) (Pisani et al., 2020). To overcome this critical issue, the recommended antibodies like anti-IL-6 antibody tocilizumab and Siltuximab under the clinical trials. Nevertheless, care should be taken for the effective control and suppression of innate immunity associated cytokine (Pisani et al., 2020). Nano based systems plausibly counteract these critical issues and might have the potential to improve the specificity and controlled immunosuppressant delivery. It could be attained by the fine-tuning of the nanocarrier systems surface charges that improve the encapsulation with the required loading of the anti-immunosuppression drugs, pertinent to reduce drug dose as well as the non-target drug distribution, and possibly undesirable consequences. Further, it can deliver targeting specific immune subpopulations to avoid the provocation of other immunological responses. Previous encouraging results of the Octadecylamine functionalized nanodiamond with dexamethasone able to demonstrate the anti-inflammatory and pro-regenerative activity in human macrophages under in vitro condition. Additional, it has also reduced the macrophage infiltration and controlled expression of iNOS and tumor necrosis factor (TNF)-α (proinflammatory mediators) (Weiss et al., 2020). The occurrence of the ordered structure, controlled porosity with surface charges on the nano dimensional carbon materials has exhibited the effective adsorption of IL-6 and TNF-α (Weiss et al., 2020). Plausible use of this kind of Nanosystem against the early stage of sepsis, where effectively complete removal of pro-inflammatory cytokines from the bloodstream, would reduce and eradicate the mortality of the critical Covid-19 patient (Weiss et al., 2020). Therefore, nano-based therapeutics could attain specific target site delivery of immunosuppressive drugs in a controlled inhibition or provoke the specific immune cell subpopulation, results in limiting the complication in a cytokine storm.

    Novochizol™ along with the Bioavanta-Bosti’s academic partners developed a fully biocompatible chitosan-based nanoparticle for safe and effective drug delivery technology. This could ensure sustained-release without systemic distribution when strongly adhere to lung epithelial tissues. Currently, this concept is under the extensive preclinical testing stage. Their synthesis method comprises of the two-step activation of linear chitosan, the active ingredients (small molecule or biologic) in single or combined form. Due to the intramolecular reaction, the active ingredients encapsulates and form the nano dimensional structure that targets the intra-pulmonary delivery system (Figure 8).

    FIGURE 8

    

    Figure 8. Biocompatible chitosan-based nanoparticle drug delivery technology from Novochizol^TM (Re-produced with permission from Novochizol).

    Role of in silico in Nanomedicines

    Recent advancement in the computational field, artificial intelligence, and machine learning are elevating the simulation and modeling process that could predict the possible evaluation of nano theranostics and nanotoxicology response. Based on the molecular targets (3CLpro and PLpro- Viral protease, TMPRSS2-host cell produced protease, RdRp- RNA polymerase, viral S protein and host receptor ACE2) (Chauhan G. et al., 2020) and related information (either from the sequences or structural information) it is possible to predict the lead compounds (repurpose the existed antiviral molecules or new ligand molecules) and antiviral peptides, from the Zinc database, FDA approved drugs and CoronaDB-AI (Keshavarzi Arshadi et al., 2020; Lin et al., 2020). Further, the procedure is optimized by the scrutinizing of colloidal particle size determination, algorithms to establish dosimetry for inhalation toxicology, computational OMICS and nanoscale-quantitative structure-activity relationships (nano-QSAR), able to propose the refined nanomedicine with minimizing the utilization of resources. This new infesting technological era would facilitate to develop benign nanomedicine within the short span of period. In the future perspective of nanomedicine, the advantage of the futuristic technology of artificial intelligence tool can be taken for rapid screening of lead compounds, possible bioactivity screening/prediction and the rapid evaluation of these compounds in specific animal models, which enable to improve and validate the nano dimensional combination therapeutics.

    Practical Snags in Bio-Nano Interface Technology Related to Covid-19

    When the biological nano dimensional surfaces and synthetic nano dimensional material surfaces, are interfaced, there are numerous physicochemical interactions such as Van der Waals forces, electrostatic, solvation, solvophobic, and depletion forces. These interface forces are influenced by the surrounding environmental medium. The most probable obstacles arise in these circumstances. The precise upscale in the industrial process and durability of the stable nano dimensional products are hindering the direct application in the field of pandemic situation. In the lateral flow assay interaction of biological functional nano dimensional materials with the engineered nanomaterials convert the signal transducers (optical, electronic, magnetic, catalytic, surface plasmon, piezoelectric, and plasmonic photothermal) effectively and can be able to provide a rapid diagnosis of Covid-19. Yet, interfacing the nano dimensional materials in real-time biological complex environments are snag and could provoke protein denaturation, steric hindrance, and unspecific adsorption (Nel et al., 2009). These undesirable side effects might be revealed for estimating the durability and stability of the nano products. Nano formulated repurposing drugs and vaccines should undergo the additional clinical trials concerning the quantification of the nanomaterials in each cellular process of administrable initial concentration during the route of exposure, required concentration at the target organ and liberation or disintegration of carrier and drug (Genchi and Ciofani, 2019; Riediker, 2020). Above mentioned obstacles can be overcome with the detailed bio-nano interface technology studies. The first impressive Covid-19 vaccine candidate enters the trial is the lipid nanoparticle-based mRNA delivery. Therefore, the futuristic bio-medical field will utilize the sustainable nanotechnology to combat disease effectively.

    Conclusion

    The interface between the functional biological molecules with the nanotechnology principles and techniques paves the understanding, development and improvement of advanced biotechnological process and products development like implantable medical devices, nano-robots, and the use of biological molecules in nanodevices. To look for detailed biological interaction process, the observations at the nanoscale level would give a promising dimension of understanding that involves the recognition, differentiation, memory, and storage of cellular process function effectively as a collective response that can control the complex macro living systems. A similar way of understanding the nature and behavior of virus at the nanoscale level would reveal the effective control or eradication strategy. The coherence of material science provides an inevitable contribution to the biological system, which is found to be a useful tool to fight against invisible battlefield effectively. In the future perspective niche, there is plenty of room at the Bio-Nano interface.

    Author Contributions

    S-KK conceived the idea and wrote the manuscript. He had re-drawn the images and got permission for Figure 8 from the Novochizol^TM.

    Funding

    S-KK would like to acknowledge the Conacyt-México: CALL 2020-1 Support for Scientific Research, Technological Development and Innovation in Health Projects in the Event of Covid-19 Contingency. Proposal number: 312032 (Under consideration, not yet approved).

    Conflict of Interest

    The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    Acknowledgments

    S-KK would like to acknowledge, Ernesto Lugo Ledesma, Director of Technology Institute of El Llano Aguascalientes (ITEL) and Enrique Fernández Fassnacht Director General of National Technology Institute of México (TecNM) for their constant support and facilities to promote the research activities.

    Supplementary Material

    The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnano.2020.586250/full#supplementary-material

16. Immunity Community Invitation
    COVID-19 was over for 30 hospital patients, many over 50, in just 3 days, after a 15-year quest by a Ph.D. organic chemist who has 30 patents in 85% of the world. The FDA, generally regarded as a safe, chief ingredient, is an organic, plant-derived nano molecule, unlike any superfood in history. Suspended in a nano-emulsion, 3-ounce bottle, it’s safe to use with any medication for any person of any age or condition. The mighty, yet tiny, nano manna bottle lasts 30 days.  The CEO, inventor, has 35 worldwide patents. The manna nanoparticle molecule averages 48 nanometers in diameter, half the size covid-19 virus. Unique among master molecules like h20, vitamin C, cannabidiol.Evidence shows it may upgrade all DNA RNA with no invasive synthetic ingredients, cleaning, restoring, and continually coaching all cells to excel in all known and unknown dimensions. While downgrading all foreign agents and predatory organisms with a path of least resistance to optimum immunity life.Immunity community candidates have ideally licensed health professionals. As of 21/2021, we comply with all regulatory agencies to the best of our ken. Sovereign tribes are a priority.The Navajo Nation, one of the largest, with 172,000 residents had the highest infection rate per capita in 2020. Other priorities are CA, PS, NY, and Florida. As world media forecast a greater wave of viral speed global health and economic systems failure; the wave to trump the gloom with an all cells well global boom, will be elected by millions in 2021 and billions in 22 to a 23 unprecedented quantum leap; when climate extinction fatalists say humanity, days are over and humanity days are over in the 6th-grade extinction.The global stimulus check, green deals, resets, tax relief, and other innovations; will be amplified exponentially when an irresistible tipping point of conscious users utilizes the deceptively simple formula, based on the molecules that helped the first cell, survive and thrive in all inner and outer conditions.Harvard medical school reports Americans to get 22 teaspoons of sugar daily in denatured food and drinks totaling 70 pounds yearly. The Lundbeck foundation shows non-beneficial viruses and bacteria need human cell membrane sugar to thrive.The convenient truth is the world’s most unprocessed sugar Molecule, from a proprietary process in an FDA certified lab, does the extreme opposite.The proliferation of millions of antibodies in 5 days, producing super well cells, out-races the production of abnormal cells; envisioning a viral growth of post pandemics wellness. On 02/27/2020 is a global immunity community launch on a media outlet seconds only to GAIA. Look for the next 9 press releases in this exclusive series only brought to you by iCrowdNewswire.Antibodies are what counter all infections and repair all cells. These glycoproteins are on the surface of b-cells. The IgG molecule is 13 nanometers and is 75% of the 1 trillion different antibodies army, in everybody. There are 10 billion customized antibodies in each person’s community of cells that’s 2 billion more than the number of people in the world community.Many antibodies aren’t activated in your life. Evidence shows our nano molecule may activate the entire army sleeping within you to defend, amend and ascend every cell. The IgG antibodies are the dominant class in the immune army. Most immune tests look for the number of Igg. When nano-soma consistently shows the continuous activation of all antibodies, why is the testing business needed?For a short time, we are giving tribal decision-makers up to 108 bottles of nanosoma. The Navajo Nation, one of the largest tribes, had the highest infection rate per capita last year. This is the world’s first planned nana demic and after a 15-year quest, the nana molecule moon shot is launching today as this release goes out. The manna pandemic, got speed, will go beyond viral.For all info text only 3 lines to 936-718-2747. No calls will be taken.Exclusively by iCrowdNewswire.com
17. Press Release pt. 2Mass adoption education warp speed benefits for this experience evidence based rollout were seeded on the 2/1,first of “Ten Commandments “press series for true ,new ,modern manna dispensation with the vision of 7 generation all nations compensation restoration and a nature given cellular sovereign all nations.Covid over and post pandemics,nature science ;intrinsically has no adversaries;only the uniformed;we stand ready to inform;as they choose.The data tsunami of the super immunity science has few doubting Thomas types ;and new validation and 1000 anecdotals arrives weekly.Status quo media will be your last resort source for this 360 human regeneration science for a global safe climate based on mass regeneration of next steps in human evolution for an economy and global culture that’s local,fair and exponentially dynamic.There are 10 websites on this universal nano plant post pandemics.With 5 daily,no obligation nano recorded telemed zoominars.The tiny yet mighty ,millennium,tipping point may be as little as 10% of 3% of any community,consistently using a patented,anti viral,nano organic.sub lingual spray,for $2 a day;that’s been commercially available for 6 years,in full compliance with national regulatory agencies.Text only 936-718-2747,for all professional enquiries and the covid Ebola over 3rd part study and the 1/28-28, global wellness inauguration telethon with 13 licensed health professionals from 3 continents.Like the data breach,found by fire eye;our bio nano secures all bio data ;with 24/7 upgrades,in real time.An M.I.T.,PHD,after 12 years r&d ,says glycophosphate molecules overwhelm respiratory immunity,disrupting the innate immune component and imbalancing the adaptive side,preventing homeostasis and make a stimulus check for category 5,cytokine storms,electing unfriendly viral takeovers of people,nations and the planet.Postpandemics science is proven,safe,affordable and easily distributed on the scale needed,for super human immunity and all round health with no interference with any pharmaceutical prescriptions.For extreme validation see Jennifermargullis.netContaminated populations choose more contaminated paths when all cells are not well.Community immunity via our patented organic sublingual spray has high wire highest priority in California, Texas, New York and Florida as of 1/25. See npr.org1 study showed oxidized vitamin C ;in vitro;was made;in the user up to 10 grams.These,and other.consistent benefits,are seen in no other health science,nano or not,anywhere on this earth;thus this is the most disruptive,beneficial milestone we can conceive of .This is the single most, all in one ,non synthetic,universal organic,plant food medicine,we are aware of.“The doctor of the future will give no medicine, but will interest his patient in the care of the human frame, in diet and in the cause and prevention of disease.” – Thomas Alva EdisonThe 2009 virus was the 21st century’s first pandemic and this flu strain is still a seasonal virus.the bradkinin molecule is the eyes of the covid cytokine storm.We’re planning a rollout in Brazil;where 212 million are a power house for plant based innovation;says Ny times,12/27/2020,lauding felipe  Neto with 40 million you tube subscribers, tv host Xuxa Meneghel, good food institute Brazil, and Fazenda Futuro.On March fourth, there will be a telethon on the new nanoplandemic.See the online article on Mosaic-networx.com;this is why video is the most engaging type of content volunteers may use.
18. Release 3

    Life molecules gifted 13 formulas to Iowa leaders.

    Post Pandemics living nano,organic plant formula activates all cells immunity as no other science.

    Super health is in the underutilized receptors in the nucleus of each human cell,the master key ,to potentiate all friendly viruses and bacteria,via the alpha omega genetics of all life kingdoms and their unlimited genome potential to survive,revive and thrive in virtually any inner or outer environment or terrain.

    N.I.H found 48  receptors in each cells’ nucleus.

               

    The 48 nanometer molecule binds to the 48 nuclear receptors within each of the human body’s 1.6 quadrillion cells. It binds to vitamin d receptor sites, releasing up to ten grams daily, for an antiviral stimulus check relief package.of the 6 main immunoglobulins and interferons for a category 6 ,perfect storm,chain reaction of super immunization activation.

    The innate immune layer, your first line of defense neutralises viruses etc. The adaptive immune I.d.’s them custom making antibodies with a bio database recognizing them.

    pubmed says the miracle molecule kept the first cell well ,2 billion years ago:preceding all traditional medicine East and west with nature’s original best.

    

    129 billion masks surpassed cell usage. Global mandated mask vax is likely.

    Metamasks, kandymask, and puremask are certified by the gold standard of protective mask.

    Particulate Matter 2.5 (PM2.5), refers to tiny particles  in the air that are two and a half microns in width. One micron is one-thousandth of a millimeter, there are 25,400 microns to one inch, up to forty times smaller than a human hair. Particles less than 2.5 microns are so small that several thousand of them could fit on the period at the end of this sentence.

    129 billion disposable masks used monthly make reusable masks a must. 3000 2 microns sized particles are in 1 period.

    Ga,TX,NV, and WY have the lowest vax ratings.

    The invisible rainbow links many modern illnesses to emf. See eesystem.com

    Priority Postpandemics pillars are nano ceutical,nano masks,nano septic surface tech and dvm.oils stopping Covid in 3 seconds in a level 3 lab.

    Femto science makes nano look large, reinventing immunity with non-invasive diagnosis, therapeutics, and super water. See kmzholding.net and zymoresearch. A nanometer is 10 times the width of an atom. A femto particle is 1 million times smaller than a nanometer. Our scalar enhanced molecule is available.

    The ant has a real,nano cpu. 10 times smaller and  100 times more powerful than any before it.

    Learn nano life tech ,though conditioned to not learn fast;unlike covid. Immune systems cure or cause disruptions like environmental corruption.

    Covid in vitro, nature’s food nano dwarfs synthetics needing no costly drug trials, with endless uses.

    On 2/7,a representative of 170 billionaires asked for the Postpandemics gifting.

    This relief is worth more than America’s G.D.P. We will give a complimentary Viral Victory to 50 people.

    Consciousvitality.com hosts a 2/27,2/28,3/4 Postpandemics solutions now, science panel telethon hosting a viral victory now with medical doctors. The miracle molecule sublingual spray is available in an affiliate marketing model option.

    Text only (936)718-2747 with no more than three lines to get a reply.1millon bottles may March 4th on inauguration day.

    These statements have not been evaluated by the Food and Drug Administration. These products are dietary supplements, are not drugs, and not intended to diagnose, treat, cure, or prevent any disease.Results vary and may not be representative of the experience of others. Information and statements made are for educational purposes and are not intended to replace the advice of your doctor. If you have a medical condition or health concern, see your healthcare provider.

19. Release 4 Draft
    

    Immunity community regeneration

    The plant molecule sublingual spray that got 30 covid patients past covid in 3 days may activate super health for all kingdoms of life.

     

    Nano immune naturals are super absorbable, low cost manufactured, balancing all 48 receptors in the nucleus of all cells. PubMed identifies lipid molecules making the first cell healthy 4 billion years ago.

     

    Of 50,000 combinations, a PHD organic chemist found the core molecule, nano stabilized it at 48 nanometers in diameter, as an FDA, recognized, organic safe food. 1 nanometer is 10 times an atom size.

    

     

    Novax sold ten million synthetic lipid vaccines to New Zealand with one billion in warp speed funds to vaccinate 100 million by 2022.

     

    Biospace.com

    

     

    Inhaled particles are cleared from the lungs by innate immune systems like macrophages and phagocytes. Nanoparticles can super train immune cells to target viral agents

    

    Gold nanospheres with a protective polymer at the University of Geneva upgrade the immune system, eliminating cancer cells by crossing the blood-brain barrier. Nanopartz.com, in fourteen hundred publications, uses silver, platinum and titanium. Gold nanoshells are surface plasmon resonant nanoparticles with a silica core that fit in a gold shell. Nanotraps block and macrophage recycle viruses.

    

     

    kmzholdings.net make nano look like Shaq.

    

     

    The first manna, may be used with any medication, has a 3-year plus, room temperature shelf life and is patented in 85% of the world. At $2 a day,1 month supply, it’s made by the ton, shipped globally.

     

    500 pages of external studies, show DNA deficits in people and other life forms may be solved by a super immunity longevity to compliment and uplift all nature, obsoleting denatured science for a post pandemics global wellness world. –It’s marketed in an affiliate option, with 10,000 bottles housed for America.

     

    The scalar improved version is available to those who show they’ll steward the millennium green deal science.

     

    3% made the American revolution. 10% of 3% of America using the Methuselah molecule may chain reactivate, global evolution to extinguish the 6th extinction.

     

    Post pandemics homegrown may start in Iowa with those showing true innovation receptor sites for global health gone viral for a never before seen, people planet profit spirit science standard, full disclosure.

     

    7 generations adoption education perpetuation needs students, volunteers and entrepreneurs from all walks. Daily custom recorded zoominars are for qualified action takers. Natural nano mask makers are JV options with other, non-synthetic, nano tech liberation science advocates, in any community.

     

    N95 masks filter to 300 nanometers covid is 100 as bio and inanimate pollutants grow smaller the demand remediation at their scale. Kandymask.com offers $2,000 to a charity of your choice if you prove there’s a better mask.

     

    See 4cair and nanofitmask

     

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    It’s said that no pathogen can resist UV in some masks.

     

    Scalar enhanced manna is here. Lipid super natural nano is the sweet nothing that may mean everything, in these times

     

     

    These statements have not been evaluated by the Food and Drug Administration. These products are dietary supplements, are not drugs, and not intended to diagnose, treat, cure, or prevent any disease. Results vary and may not be representative of the experience of others. Information and statements made are for educational purposes and are not intended to replace the advice of your doctor. If you have a medical condition or health concern, see your healthcare provider.

     

    Inquiries, text only (936)718-2747 with a three-line max bio in order to get a reply.

20. Post Pandemics 2/19 Zoominar

     

    Plan post pandemics living now on recorded, no obligation zoominar. Attend by reading article 315 on goldenopportunitiesdevelopment.com and texting 3-line bio only maximum, to (936)718-2747.

     

    The 48 nanometer, plant molecule can’t be compared to any food, supplement or drug.

     

    It’s the only molecular compound balancing all 48 nuclear receptors in the nucleus of all cells of all life kingdoms and activates the best genetic potential of people, animals, plants and biota, always favoring non predatory agents, regardless of mutations and environmental pathogens.

     

     

     

     

    A femto particle a trillion trillion times more effective than nano particles, works subatomicly. Pico items ,1000 times smaller than nano are on the market.

     

    Pfizer makes a drug version lipid for stem cells for youngevity; 3 people in the world know where they stemmed from.

     

    Masks and vax are exponentially mandated; wear the nano best and pass the nano immune nutraceutical test.

     

    Priority post pandemics pillars nano ceutical, nano masks, nano septic surface tech and DVM oils stopping Covid in 3 seconds in a level 3 lab. Kmzholdings.net has the new diagnosis standard for all health assessments.

     

    Nanosfoundation.org ‘s nonprofit nano med, mask and more brings post pandemics affordability, mirroring the nano food med. Their 106,000 nanofibers in a mask equals a hair’s width.

     

    PKN95 mask-hopehelpsupply.com, 4cair.com’s electro spun non weave mask is 6 times more breathable than N95. Bioaid.com, silvertekusa.com, nano air, rapidmask2.com and microbeformulas.com are nano milestone, post pandemics options like worlddevelopement.com, 53 million mask donation,1 million which could protect Iowa.

     

    Zioshield, claros.com is 100 washables. Inovenso.com brings electro spin for modular scale up nano safe America. Halomask.io has fifteen miles of bamboo nanofiber per mask with 20% referral fee.

     

    Utah University verifies the nano resonant lipid molecule is 4,000 times the effectiveness of remdesivir, 6000 that of hydroxychloroquine, has no side effects, no toxicity at suggested dosages and doesn’t contradict any pharmaceutical. It may enhance any prescription, is affordable, easily storable and mass market ready anywhere.

     

    Vitamin D regulates 2000 genes. Most Covid patients are deficient. 85% of Americans are deficient. Vitamin D deficient males are, twice as prone to heart attacks.

     

    Biobased.com left nano for Pico scale and may be the most effective way all cell immune youngevity. If you won’t unlearn, you don’t learn. Will Pico replace virus civilizations for .003 cebra? Biobased.us seeks distributors and licenses to large companies.

     

    Carbions never failed mitigating any virus or pathogen in people, plants, animals. Covid over 6 hours, crops tripled, trees grown double fast, 100 Morgellons cases solved.

     

    The new super charged 93% carbon, from plants formula; has 5 sextillions super anti-viral

    atoms of nature’s alpha omega life quality for your best living experience and climate. Halo life.io mask has fifteen miles of nanofiber.3 Pico atoms will make a wall around America,1.35 miles high

     

    The ant has a real, nano CPU. 10 times smaller and 100 times more powerful than any before it.

     

     

     

     

    These statements have not been evaluated by the Food and Drug Administration. These products are dietary supplements, are not drugs, and not intended to diagnose, treat, cure, or prevent any disease. Results vary and may not be representative of the experience of others. Information and statements made are for educational purposes and are not intended to replace the advice of your doctor. If you have a medical condition or health concern, see your healthcare provider.

     

    Inquiries, text only (936)718-2747 with a three-line max bio in order to get a reply. Consciousvitality.com, a 25/03 post pandemic science panel.

    goldenopportunitiesdevelopment.com, article 315. Advocates may have press release services, gratis.

21. One way of reviewing the score card is 300,000; America allocated  $1 trillion for covid in 2020, authorized a $900 billion relief package on 12/21/2020, lost 200,000 people, may lose 500,000 by April and no vaccine provider in the world will agree in writing to pay for 1 side effect, to any vaccine user, or any pharmaceutical, for that matter. Avoiding all anti & vaccine adversarial divisiveness and geopolitical, colonial, racial and economic inuendos; it’s proposed herein, given the abundant, independent, tier 1, clinical studies on nanosoma or metadichol, for extreme safe, effective, affordable anti-viral benefits for treatment and prevention of covid-19, Ebola, the Zika virus and conditions from cardiovascular to cancer; everyday citizens and influencers from America, now the leading locale for covid cases, fatalities and other economic and health care provider cofactors are invited to evaluate thenanosoma.com site from every perspective; if a product is purchased to trial.     ​                                                                                                                                                         The author of this article asks that this affiliate code is referenced – magicdichol.com/store/mdusa/?aff_id=4509. Text (936) 718-3747 for media, science, business related information and personalized zoominars, Skype and 3 way, no-obligation conferences.
22. The true immunity stimulus check will be covid etc is over, and the many proposed remedies, that may show they’re worse than the problem after it’s too late to reverse either.
23. 12/20/2020, 364 days after the first covert release, I spoke to Raghu Raghavan, PhD organic chemist of 25 years, no longer employed by mega pharmaceutical companies and 12 years self funded researcher and sole developer of the Nano Soma growing tribe of products inspired by the oldest science culture,the newest Nano tech and now humanity’s and Gaia’s greatest challenge to the point of extinction of any species including people.
24. He shed light on lipid bio and astrobiology and a litany if anecdotals from mds, immunologists and an undisclosed world leader or 2.
25. The plandemic documentary maker has had Nano Soma 3 weeks and after getting 2 billion viewers in 10 days, plans sequel 3; is hue manna demic what it will be.
26. consciousvitality.com will likely make the news scoop of the epoch, with the Nano Soma cosmic disclosure that counts on its 13 days away from a minor political even, by hosting a nano soma, self-appointed ambassador on their not to be missed, live Nano Soma international interview. 1/7/2021, 9pm to midnight show with surprise guests and cameos by prominent licensed health professionals and a more than live call in format.
27. All food needs the sun, water and oxygen. Food RNA & DNA dials in human RNA & DNA; the nano size lipid molecule of 50 nanometers is 1/2 the size of the most famous virus and does some fast talking to the 48 nuclear receptor that manage the entire l-genomic code which is up to 90% a good bacteria and benign viral symbiosis. See nanoojas.net.
28. there are 20,000 genes in the body and 360 genes for good viruses and bacteria;the combined total is 7 million genes all opitimised by our specific nano molecule which is the original molecule in the key of life.
29. The inventor is an Oregon state PhD in the orthomolecular tradition of Linus Pauling, the only recipient of two unassisted Nobel prizes and vitamin C molecular master biochemist and icon of thousands of true, complementary alternative medical doctors in over 190 countries today.
30. Raghu Raghavan has verified that his nano lipid molecular food recycles oxidized vitamin c which evidence shows that many animals resist cancer since they haven’t lost the genetic ability to make vitamin C like people.
31. The American revolution starting April 19,1776,was won with only 3% of the original coloneed actively participating.given the depth and breadth of the liberation of every human cell ,the true tsunami evolution of all cells may start with 10% of 3% of Americans voting for their own keys with 90,000 using nanosoma for 30 days.large scale health trials start at 30,000 participants. This would be over the top with manna drops for under $2 a day spray.The top 3 true sovereign nations in America alone,such as the Onieda, Navajo and Mohawk could reinvent civilization and show the way to an unimaginable un manifest destiny as never seen on earth;by trialing the original good medicine molecule.Who will quantum quarter back a post pandemic civilization win with nature’s highest life quality science?
32. Returning to your metagenome, you have 4 million good bacterial genes for every 1 human gene.1 picogram of the nano lipid spray has increased telomere length 16 times; a direct anti aging bio marker. Raghu is 69 and has the telomeres age of a 50 year and out plays 20 year olds in badminton 2 hours a day, 3 days a week.
33. After countless lifetimes Nano Soma has warp sped its way here billions to find the first 13 first responders while billions are led to outertainment criticizing and being hypnotized by outer phenomena. the real adventure and true human evolution is the sovereign secret of all human cells guarded by the 48 nuclear receptor sites on the surface skin of each cell as hue manna beauty is more than skin deep. The nano soma plant molecule galactivates all 48 tipping points of genetic optimization for all 20,000 genes of which 200 are most essential to human evolution and wellness in any environment; however viral and or artificial. No other single molecule can do its perfectly symmetrical shaped moleculdharma; be it vitamin C, D, cannabidiol. C-60, glutathione, colostrum, hydrogen, oxygen or nitrogen. The nanosoma molecule is a carbon, hydrogen, oxygen atoms composite.90% of human genes are beneficial viruses and genes so logic says we are designed to interface with all microbiota, survive and thrive with the most sophisticated tech in creation; the human body or vehicle of ultimate evolution and fulfillment as the rig Veda operators manual says.The nipah super infectious and more deadly than covert 20 and the yara with 80% of never before seen genetic code aren’t nearly as important as the 30 day trial experience of the nanosoma keys to your cellular sovereign interior castle.The times demand each of us do our part to meet history’s and surpass the greatest challenges by using the universal key to the citadel within each of our 1.6 quadrillion cells holding the health wealth joy beyond our mundane attachments to the countless illusions so well sold to us for lifetimes.Each of us carries a minimum of 100 trillion good and ungood viruses and bacteria from 6 generations-120 years; nano soma returns the wisdom of each cell to know the difference and work with the pro biota and the naysayers. For select enquirers; we will share a recent Utah University, National institute of health study verifying the nano resonant lipid molecule is 4,000 times the effectiveness of remdesivir, 6000 that of hydroxychloroquine, has no side effects,no toxicity at suggested dosages and doesn’t contradict any pharmaceutical prescription. evidence shows it may enhance any prescription and it’s affordable, easily store able and mass produce able in any country; provided the water in the formula and production, meets the highest known standards.
34. Hundreds of prominent labs in 13 countries know the Nano lipid molecule by the metadichol name, an anagram for methodical remedy for any cellular condition in people and animals. Labs aren’t oriented to sharing planetary wellness turn around news; ethically influencers are and very few have these reports and more importantly, the Nano Soma pray in a spray experience. 5 good
35. In a recent study, Metadichol has also shown to inhibit SARS-COV2 (Covid-19). Metadichol has the ability to break down the lipid envelope regardless of the type of virus inside. Once the envelope is broken down, the virus is destroyed.Metadichol® is the first of a breed of molecules that moves the goal post from the concept of ‘one drug, one target’ toward simultaneously targeting multiple targets, that can potentially lead to successful treatment of many diseases. Given the safety profile of Metadichol®, it would not only mitigate thyroid disease but prevent it and reducing the burden on healthcare budgets worldwideMetadi