COVID-19 therapy approaches and vaccine development: the role of nanotechnology

Document Type : Review Paper


1 Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Service, Yazd, Iran


Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) caused an outbreak in Wuhan, China in December 2019, and right after that SARS-COV-2 spreads around the world infecting millions of people worldwide. This virus belongs to wide range virus family and cause moderate to severe signs in patients, the Sars-COV-2, can spread faster than others between humans and leads to severe outbreak. Recently researchers succeed to develop various vaccines including inactivated or attenuated viral vaccines as well as subunit vaccines to prevent SARS-COV-2 infection. Nanotechnology is advantageous for the design of vaccines since nano scale materials could benefit the delivery of antigens, and could be used as adjuvants to potentiate the response to the vaccines. Indeed, among various vaccines entered clinical trials, there are mRNA-based vaccine designed based on lipid nanoparticles. Herein, we summarized SARS-COV-2 structure, pathogenesis, therapeutic approaches and some COVID-19 vaccine candidates and highlighted the role of nanotechnology in developing vaccines against SARS-Cov-2 virus.


1.Le TT, Andreadakis Z, Kumar A, Roman RG, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5): 305-306.
2.Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020; 38(1):1-9.
3.Eurosurveillance Editorial T. Updated rapid risk assessment from ECDC on the novel coronavirus disease 2019 (COVID-19) pandemic: increased transmission in the EU/EEA and the UK. Euro Surveill. 2020; 25(10).
4.Kahn JS, McIntosh K. History and recent advances in coronavirus discovery. The Pediatric infectious disease journal. 2005; 24(11): S223-S227.
5.Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. New England Journal of Medicine. 2020.
6.Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 vaccines at pandemic speed. New England Journal of Medicine. 2020; 382(21): 1969-1973.
7.Amanat F, Krammer F. SARS-CoV-2 Vaccines: Status Report. Immunity. 2020; 52(4):583-589.
8.Lancet T. Global governance for COVID-19 vaccines. Lancet (London, England). 2020; 395(10241): 1883.
9.Seah I, Agrawal R. Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals. Ocular immunology and inflammation. 2020; 28(3): 391-395.
10.Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. Journal of Microbiology, Immunology and Infection. 2020.
11.Elfiky AA, Mahdy SM, Elshemey WM. Quantitative structure‐activity relationship and molecular docking revealed a potency of antihepatitis C virus drugs against human corona viruses. Journal of medical virology. 2017; 89(6): 1040-1047.
12.Hemida MG, Alnaeem A. Some one health based control strategies for the Middle East respiratory syndrome coronavirus. One Health. 2019; 8: 100102.
13.Báez-Santos YM, Mielech AM, Deng X, Baker S, Mesecar AD. Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus. Journal of virology. 2014; 88(21): 12511-12527.
14.Organization WH. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV)infection is suspected: interim guidance. World Health Organization; 2019.
15.Ibrahim IM, Abdelmalek DH, Elshahat ME, Elfiky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction. Journal of Infection. 2020.
16.Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273.
17.King AM, Lefkowitz E, Adams MJ, Carstens EB. Virus taxonomy: ninth report of the International Committee on Taxonomy of Viruses: Elsevier; 2011.
18.Lefkowitz EJ, Dempsey DM, Hendrickson RC, Orton RJ, Siddell SG, Smith DB. Virus taxonomy: the database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic acids research. 2018;46(D1):D708-D17.
19.De Haan CA, Kuo L, Masters PS, Vennema H, Rottier PJ. Coronavirus particle assembly: primary structure requirements of the membrane protein. Journal of virology. 1998;72(8):6838-50.
20.Woo PC, Huang Y, Lau SK, Yuen K-Y. Coronavirus genomics and bioinformatics analysis. viruses. 2010; 2(8): 1804-1820.
21.Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012; 4(6):1011-1033.
22.Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78: A cell’s response to stress. Life sciences. 2019; 226: 156-163.
23.Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005; 35(4): 373-381.
24.Li J, Lee AS. Stress induction of GRP78/BiP and its role in cancer. Current molecular medicine. 2006; 6(1): 45-54.
25.Quinones QJ, Ridder GGd, Pizzo SV. GRP78, a chaperone with diverse roles beyond the endoplasmic reticulum. Histology and histopathology. 2008.
26.Rao RV, Peel A, Logvinova A, del Rio G, Hermel E, Yokota T, et al. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS letters. 2002; 514(2-3): 122-128.
27.Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426(6965): 450-454.
28.Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme–related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation research. 2000; 87(5): e1-e9.
29.Li F. Structure, function, and evolution of coronavirus spike proteins. Annual review of virology. 2016;3:237-61.
30.Sola I, Almazan F, Zuniga S, Enjuanes L. Continuous and discontinuous RNA synthesis in coronaviruses. Annual review of virology. 2015; 2: 265-288.
31.Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020; 12(4): 372.
32.Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. New England Journal of Medicine. 2020.
33.Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research. 2020;30(3):269-71.
34.McCreary EK, Angus DC. Efficacy of Remdesivir in COVID-19. Jama. 2020;324(11):1041-2.
35.Yoo J-H. Uncertainty about the Efficacy of Remdesivir on COVID-19. J Korean Med Sci. 2020;35(23).
36.Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.
37.Que T, Wong V, Yuen K. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.
38.Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine. 2020.
39.Zhou D, Dai S-M, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. Journal of Antimicrobial Chemotherapy. 2020.
40.Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. Journal of critical care. 2020;57:279-83.
41.Kalil AC. Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics. Jama. 2020; 323(19): 1897-1898.
42.Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama. 2020; 323(18): 1824-1836.
43.Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clinical Infectious Diseases. 2020.
44.Soo Y, Cheng Y, Wong R, Hui D, Lee C, Tsang K, et al. Retrospective comparison of convalescent plasma with continuing high‐dose methylprednisolone treatment in SARS patients. Clinical microbiology and infection. 2004; 10(7): 676-678.
45.Wang L-s, Wang Y-r, Ye D-w, Liu Q-q. A review of the 2019 Novel Coronavirus (COVID-19) based on current evidence. International journal of antimicrobial agents. 2020:105948.
46.Yu M, Wu J, Shi J, Farokhzad OC. Nanotechnology for protein delivery: Overview and perspectives. Journal of controlled release. 2016; 240: 24-37.
47.Li B, Zhang X, Dong Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 2019;11(2):e1530.
48.Hirano T, Murakami M. COVID-19: A new virus, but a familiar receptor and cytokine release syndrome. Immunity. 2020.
49.Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet (London, England). 2020;395(10229):1033.
50.Yang Y, Shen C, Li J, Yuan J, Wei J, Huang F, et al. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. The Journal of allergy and clinical immunology. 2020.
51.Al-Lawati H, Aliabadi HM, Makhmalzadeh BS, Lavasanifar A. Nanomedicine for immunosuppressive therapy: achievements in pre-clinical and clinical research. Expert opinion on drug delivery. 2018;15(4):397-418.
52.Abd Ellah NH, Gad SF, Muhammad K, E Batiha G, Hetta HF. Nanomedicine as a promising approach for diagnosis, treatment and prophylaxis against COVID-19. Nanomedicine. 2020;15(21):2085-2102.
53.Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama. 2020;323(11):1061-1069.
54.Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine. 2020.
55.Graham BS. Rapid COVID-19 vaccine development. Science. 2020; 368(6494): 945-946.
56.Wu SC. Progress and Concept for COVID‐19 Vaccine Development. Biotechnology Journal. 2020.
57.Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines—a new era in vaccinology. Nature reviews Drug discovery. 2018; 17(4): 261.
58.Zhu F-C, Li Y-H, Guan X-H, Hou L-H, Wang W-J, Li J-X, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet. 2020.
59.Mahase E. Covid-19: Moderna vaccine is nearly 95% effective, trial involving high risk and elderly people shows. BMJ: British Medical Journal (Online). 2020;371.
60.Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020;586(7830):589-593.
61.van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, et al. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. bioRxiv. 2020.
62.Ramasamy MN, Minassian AM, Ewer KJ, Flaxman AL, Folegatti PM, Owens DR, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. The Lancet. 2020.
63.Zhu F-C, Guan X-H, Li Y-H, Huang J-Y, Jiang T, Hou L-H, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. 2020; 396(10249): 479-488.
64.Sun W, Leist SR, McCroskery S, Liu Y, Slamanig S, Oliva J, et al. Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate. EBioMedicine. 2020; 62:103-132.
65.Raska MaJT, J. Mestecky, et al. DNA Vaccines for the Induction of Immune Responses in Mucosal Tissues, in Mucosal Immunology. Fourth Edition ed2015.
66.Li L, Petrovsky NJErov. Molecular mechanisms for enhanced DNA vaccine immunogenicity. 2016; 15(3): 313-329.
67.Kang TL, Chelliah S, Velappan RD, Kabir N, Mohamad J, Nor Rashid N, et al. Intranasal inoculation of recombinant DNA vaccine ABA392 against haemorrhagic septicaemia disease. Letters in applied microbiology. 2019; 69(5): 366-372.
68.Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, Mahrokhian SH, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science (New York, NY). 2020: eabc6284.
69.Yoon I-K, Kim JH. First clinical trial of a MERS coronavirus DNA vaccine. Lancet Infect Dis. 2019; 19(9): 924-925.
70.Wang J, Peng Y, Xu H, Cui Z, Williams RO. The COVID-19 vaccine race: challenges and opportunities in vaccine formulation. AAPS PharmSciTech. 2020;21(6):1-12.
71.Smith TR, Patel A, Ramos S, Elwood D, Zhu X, Yan J, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. 2020; 11(1): 1-13.
72.Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. The Lancet Infectious Diseases. 2020.
73.Cohen J. COVID-19 shot protects monkeys. Science. 2020;368(6490):456-457.
74.Palacios R, Patiño EG, de Oliveira Piorelli R, Conde MTRP, Batista AP, Zeng G, et al. Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac–PROFISCOV: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020; 21(1): 1-3.
75.Organization WH. DRAFT landscape of COVID-19 candidate vaccines. World. 2020.
76.Poland EG, McGuire DK, Ratishvili T, Poland GA. The economics of global COVID vaccine administration during a pandemic–Why continue skin alcohol preparation as a costly but ineffective practice? Vaccine. 2021.
77.Kim JH, Marks F, Clemens JD. Looking beyond COVID-19 vaccine phase 3 trials. Nature medicine. 2021: 1-7.
78.Schwarzinger M, Watson V, Arwidson P, Alla F, Luchini S. COVID-19 vaccine hesitancy in a representative working-age population in France: a survey experiment based on vaccine characteristics. The Lancet Public Health. 2021.