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  • Review Article
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Immunoregulatory nanomedicine for respiratory infections

Nature Reviews Bioengineering volume 2, pages 244–259 (2024)Cite this article

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Abstract

Immune-regulation strategies, such as vaccination and immunotherapy, are key to the prevention and treatment of respiratory infectious diseases. In particular, nanomedicines can be engineered and formulated to regulate host immunity in various tissues, including in the lungs. In this Review, we discuss the design of nanovaccines, including lipid-nanocarrier-based messenger RNA nanovaccines, highlighting engineering strategies for different administration routes, including nasal administration. We further discuss the engineering of immunomodulatory nanomedicines for the treatment of respiratory infectious diseases by blocking pro-inflammatory signalling pathways and virus entry, modulating stimulated immune cells and scavenging reactive oxygen species. In addition, we examine the funding situation for research on respiratory infectious diseases before and after the COVID-19 pandemic. Finally, we summarize future opportunities, challenges and global trends for immunoregulatory nanomedicine for the treatment of respiratory infections.

Key points

  • Nanomedicines can be designed to optimize the physical and chemical properties of immunologic agents for immune regulation in the prevention and treatment of respiratory infectious diseases.

  • Nanovaccines based on lipid and polymeric nanoparticles can deliver mRNA, overcome the physiological barriers of nasal mucosal immunity and improve the efficiency of antigen presentation.

  • Nanotherapeutics can be engineered to regulate the immune microenvironment in respiratory infectious diseases by blocking pro-inflammatory signalling pathways and virus entry, modulating stimulated immune cells and scavenging inflammatory cytokines and reactive oxygen species.

  • Research funding for respiratory infectious diseases has increased after the COVID-19 outbreak.

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Fig. 1: Nanomaterials for immune stimulation.
Fig. 2: Immune-regulating nanotherapeutics.
Fig. 3: Research funding for respiratory infectious diseases approved by the National Natural Science Foundation of China (NSFC) in the past ten years.

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References

  1. Dowell, S. F. & Ho, M. S. Seasonality of infectious diseases and severe acute respiratory syndrome—what we don’t know can hurt us. Lancet Infect. Dis. 4, 704–708 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bygbjerg, I. C. Double burden of noncommunicable and infectious diseases in developing countries. Science 337, 1499–1501 (2012).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Baker, R. E. et al. Infectious disease in an era of global change. Nat. Rev. Microbiol. 20, 193–205 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. Dong, E., Du, H. & Gardner, L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect. Dis. 20, 533–534 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mosier, D. A. Bacterial pneumonia. Vet. Clin. North. Am. Food Anim. Pract. 13, 483–493 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Bradley, B. T. & Bryan, A. Emerging respiratory infections: the infectious disease pathology of SARS, MERS, pandemic influenza, and Legionella. Semin. Diagn. Pathol. 36, 152–159 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shao, X. et al. An innate immune system cell is a major determinant of species-related susceptibility differences to fungal pneumonia. J. Immunol. 175, 3244–3251 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Zhou, P. & Shi, Z.-L. SARS-CoV-2 spillover events. Science 371, 120–122 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Abraham, E. et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit. Care Med. 28, 232–235 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. DiSilvio, B. et al. Complications and outcomes of acute respiratory distress syndrome. Crit. Care Med. 42, 349–361 (2019).

    Google Scholar 

  11. Li, K. et al. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J. Infect. Dis. 213, 712–722 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Singh, A. Eliciting B cell immunity against infectious diseases using nanovaccines. Nat. Nanotechnol. 16, 16–24 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Saunders, K. O. et al. Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses. Nature 594, 553–559 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Su, Z. et al. Bioresponsive nano-antibacterials for H2S-sensitized hyperthermia and immunomodulation against refractory implant-related infections. Sci. Adv. 8, eabn1701 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chaudhary, N., Weissman, D. & Whitehead, K. A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug. Discov. 20, 817–838 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wareing, M. D. & Tannock, G. A. Live attenuated vaccines against influenza; an historical review. Vaccine 19, 3320–3330 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Skountzou, I. et al. Salmonella flagellins are potent adjuvants for intranasally administered whole inactivated influenza vaccine. Vaccine 28, 4103–4112 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Ellebedy, A. H. et al. Contemporary seasonal influenza A (H1N1) virus infection primes for a more robust response to split inactivated pandemic influenza A (H1N1) virus vaccination in ferrets. Clin. Vaccine Immunol. 17, 1998–2006 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ninomiya, A. Intranasal administration of a synthetic peptide vaccine encapsulated in liposome together with an anti-CD40 antibody induces protective immunity against influenza A virus in mice. Vaccine 20, 3123–3129 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Roy, S. et al. Viral vector and route of administration determine the ILC and DC profiles responsible for downstream vaccine-specific immune outcomes. Vaccine 37, 1266–1276 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Mielcarek, N., Alonso, S. & Locht, C. Nasal vaccination using live bacterial vectors. Adv. Drug. Deliv. Rev. 51, 55–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Wu, Y. et al. A recombinant spike protein subunit vaccine confers protective immunity against SARS-CoV-2 infection and transmission in hamsters. Sci. Transl. Med. 13, eabg1143 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Smith, T. R. F. et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat. Commun. 11, 2601 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Narasimhan, M. et al. Serological response in lung transplant recipients after two doses of SARS-CoV-2 mRNA vaccines. Vaccines 9, 708 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Berkhout, B., Verhoef, K., van Wamel, J. L. B. & Back, N. K. T. Genetic instability of live, attenuated human immunodeficiency virus type 1 vaccine strains. J. Virol. 73, 1138–1145 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cevik, M. COVID-19 vaccines: keeping pace with SARS-CoV-2 variants. Cell 184, 5077–5081 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khalaj‐Hedayati, A., Chua, C. L. L., Smooker, P. & Lee, K. W. Nanoparticles in influenza subunit vaccine development: immunogenicity enhancement. Influenza Other Resp. Vir. 14, 92–101 (2020).

    Article  Google Scholar 

  28. Kim, C. G., Kye, Y.-C. & Yun, C.-H. The role of nanovaccine in cross-presentation of antigen-presenting cells for the activation of CD8+ T cell responses. Pharmaceutics 11, 612 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Silva, A. L., Soema, P. C., Slütter, B., Ossendorp, F. & Jiskoot, W. PLGA particulate delivery systems for subunit vaccines: linking particle properties to immunogenicity. Hum. Vaccines Immunother. 12, 1056–1069 (2016).

    Article  CAS  Google Scholar 

  30. Huang, J. et al. Nasal nanovaccines for SARS-CoV-2 to address COVID-19. Vaccines 10, 405 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hussain, A. et al. mRNA vaccines for COVID-19 and diverse diseases. J. Control. Rel. 345, 314–333 (2022).

    Article  CAS  Google Scholar 

  32. Meng, Q. et al. Capturing cytokines with advanced materials: a potential strategy to tackle COVID‐19 cytokine storm. Adv. Mater. 33, 2100012 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hotchkiss, R. S., Coopersmith, C. M., McDunn, J. E. & Ferguson, T. A. The sepsis seesaw: tilting toward immunosuppression. Nat. Med. 15, 496–497 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van de Veerdonk, F. L. et al. A guide to immunotherapy for COVID-19. Nat. Med. 28, 39–50 (2022).

    Article  PubMed  Google Scholar 

  35. Wykes, M. N. & Lewin, S. R. Immune checkpoint blockade in infectious diseases. Nat. Rev. Immunol. 18, 91–104 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Florindo, H. F. et al. Immune-mediated approaches against COVID-19. Nat. Nanotechnol. 15, 630–645 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jiang, S., Zhang, X., Yang, Y., Hotez, P. J. & Du, L. Neutralizing antibodies for the treatment of COVID-19. Nat. Biomed. Eng. 4, 1134–1139 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nasiruddin, M., Neyaz, Md. K. & Das, S. Nanotechnology-based approach in tuberculosis treatment. Tuberc. Res. Treat. 2017, 1–12 (2017).

    Google Scholar 

  39. Abani, O. et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 397, 1637–1645 (2021).

    Article  Google Scholar 

  40. The REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N. Engl. J. Med. 384, 1491–1502 (2021).

    Article  Google Scholar 

  41. Kozlov, M. Omicron overpowers key COVID antibody treatments in early tests. Nature https://doi.org/10.1038/d41586-021-03829-0 (2021).

  42. Roback, J. D. & Guarner, J. Convalescent plasma to treat COVID-19: possibilities and challenges. JAMA 323, 1561–1562 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Nguyen, P. T. N., Nho Van Le, Nguyen Dinh, H. M., Nguyen, B. Q. P. & Nguyen, T. V. A. Lung penetration and pneumococcal target binding of antibiotics in lower respiratory tract infection. Curr. Med. Res. Opin. 38, 2085–2095 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Qiao, Q. et al. Nanomedicine for acute respiratory distress syndrome: the latest application, targeting strategy, and rational design. Acta Pharm. Sin. B 11, 3060–3091 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Duan, Y., Wang, S., Zhang, Q., Gao, W. & Zhang, L. Nanoparticle approaches against SARS-CoV-2 infection. Curr. Opin. Solid. State Mater. Sci. 25, 100964 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. Doroudian, M., MacLoughlin, R., Poynton, F., Prina-Mello, A. & Donnelly, S. C. Nanotechnology based therapeutics for lung disease. Thorax 74, 965–976 (2019).

    Article  PubMed  Google Scholar 

  47. Yang, H. et al. Amino acid-dependent attenuation of Toll-like receptor signalling by peptide-gold nanoparticle hybrids. ACS Nano 9, 6774–6784 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Gao, Y., Dai, W., Ouyang, Z., Shen, M. & Shi, X. Dendrimer-mediated intracellular delivery of fibronectin guides macrophage polarization to alleviate acute lung injury. Biomacromolecules 24, 886–895 (2023).

    Article  CAS  PubMed  Google Scholar 

  49. Liu, F.-C. et al. Use of cilomilast-loaded phosphatiosomes to suppress neutrophilic inflammation for attenuating acute lung injury: the effect of nanovesicular surface charge. J. Nanobiotechnol. 16, 35 (2018).

    Article  Google Scholar 

  50. Kou, M. et al. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? Cell Death Dis. 13, 580 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, W. et al. Recent advances of cell membrane-coated nanomaterials for biomedical applications. Adv. Funct. Mater. 30, 2003559 (2020).

    Article  CAS  Google Scholar 

  52. Brahmakshatriya, V. et al. IL-6 production by TLR-activated APC broadly enhances aged cognate CD4 helper and B cell antibody responses in vivo. J. Immunol. 198, 2819–2833 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Hong, S. et al. B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen. Immunity 49, 695–708 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. Denzel, A. et al. Basophils enhance immunological memory responses. Nat. Immunol. 9, 733–742 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Kim, J. et al. Self-assembled mRNA vaccines. Adv. Drug. Deliv. Rev. 170, 83–112 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nakahashi-Ouchida, R., Fujihashi, K., Kurashima, Y., Yuki, Y. & Kiyono, H. Nasal vaccines: solutions for respiratory infectious diseases. Trends Mol. Med. 29, 124–140 (2023).

    Article  PubMed  Google Scholar 

  57. Soema, P. C., Kompier, R., Amorij, J.-P. & Kersten, G. F. A. Current and next generation influenza vaccines: formulation and production strategies. Eur. J. Pharm. Biopharm. 94, 251–263 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Nemes, E. et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N. Engl. J. Med. 379, 138–149 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Al-Halifa, S., Gauthier, L., Arpin, D., Bourgault, S. & Archambault, D. Nanoparticle-based vaccines against respiratory viruses. Front. Immunol. 10, 22 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, M. et al. COVID-19 vaccine development: milestones, lessons and prospects. Signal. Transduct. Target. Ther. 7, 146 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tiboni, M., Casettari, L. & Illum, L. Nasal vaccination against SARS-CoV-2: synergistic or alternative to intramuscular vaccines? Int. J. Pharm. 603, 120686 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. Guo, S. et al. Membrane‐destabilizing ionizable lipid empowered imaging‐guided siRNA delivery and cancer treatment. Exploration 1, 35–49 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Yang, T. et al. Efficient hepatic delivery and protein expression enabled by optimized mRNA and ionizable lipid nanoparticle. Bioact. Mater. 5, 1053–1061 (2020).

    PubMed  PubMed Central  Google Scholar 

  65. Zhang, H. et al. Aerosolizable lipid nanoparticles for pulmonary delivery of mRNA through design of experiments. Pharmaceutics 12, 1042 (2020).

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lokugamage, M. P. et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat. Biomed. Eng. 5, 1059–1068 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dilliard, S. A., Cheng, Q. & Siegwart, D. J. On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles. Proc. Natl Acad. Sci. USA 118, e2109256118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dong, Y. et al. Poly(glycoamidoamine) brushes formulated nanomaterials for systemic siRNA and mRNA delivery in vivo. Nano Lett. 16, 842–848 (2016).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kaczmarek, J. C. et al. Polymer–lipid nanoparticles for systemic delivery of mRNA to the lungs. Angew. Chem. Int. Edn 55, 13808–13812 (2016).

    Article  CAS  Google Scholar 

  71. Kaczmarek, J. C. et al. Optimization of a degradable polymer–lipid nanoparticle for potent systemic delivery of mRNA to the lung endothelium and immune cells. Nano Lett. 18, 6449–6454 (2018).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. Capasso Palmiero, U. et al. Poly(beta-amino ester)-co-poly(caprolactone) terpolymers as nonviral vectors for mRNA delivery in vitro and in vivo. Adv. Healthc. Mater. 7, 1800249 (2018).

    Article  Google Scholar 

  73. Patel, A. K. et al. Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium. Adv. Mater. 31, 1805116 (2019).

    Article  Google Scholar 

  74. Kaczmarek, J. C. et al. Systemic delivery of mRNA and DNA to the lung using polymer-lipid nanoparticles. Biomaterials 275, 120966 (2021).

    Article  CAS  PubMed  Google Scholar 

  75. Higuchi, A. et al. Material design for next-generation mRNA vaccines using lipid nanoparticles. Polym. Rev. 63, 394–436 (2023).

    Article  CAS  Google Scholar 

  76. Tseng, H. F. et al. Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and delta variants. Nat. Med. 28, 1063–1071 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Andrews, N. et al. Covid-19 vaccine effectiveness against the omicron (B.1.1.529) variant. N. Engl. J. Med. 386, 1532–1546 (2022).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, K. et al. Transmission characteristics and inactivated vaccine effectiveness against transmission of SARS-CoV-2 omicron BA.5 variants in Urumqi, China. JAMA Netw. Open. 6, e235755 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Low, J. G. et al. A phase I/II randomized, double-blinded, placebo-controlled trial of a self-amplifying Covid-19 mRNA vaccine. npj Vaccines 7, 161 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Annual R&D day. Moderna https://investors.modernatx.com/events-and-presentations/events/event-details/2022/Annual-RD-Day-2022/default.aspx (2022).

  81. Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Arevalo, C. P. et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science 378, 899–904 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  83. Miao, L., Zhang, Y. & Huang, L. mRNA vaccine for cancer immunotherapy. Mol. Cancer 20, 41 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shim, B. S. et al. Intranasal immunization with plasmid DNA encoding spike protein of SARS-coronavirus/polyethylenimine nanoparticles elicits antigen-specific humoral and cellular immune responses. BMC Immunol. 11, 65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Stemirna Therapeutics. Vaccine agent for treating or preventing coronavirus disease. WO2021159985A1 (World Intellectual Property Organization, 2021).

  86. Yang, R. et al. A core–shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal. Transduct. Target. Ther. 6, 213 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yan, Y. et al. Systemic mRNA delivery to the lungs by functional polyester-based carriers. Biomacromolecules 18, 4307–4315 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Suberi, A. et al. Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination. Sci. Transl. Med. 15, eabq0603 (2023).

    Article  CAS  PubMed  Google Scholar 

  89. McKinlay, C. J. et al. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc. Natl. Acad. Sci. USA 114, 448–456 (2017).

    Article  Google Scholar 

  90. Haabeth, O. A. W. et al. mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice. Proc. Natl. Acad. Sci. USA 115, E9153–E9161 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Petsch, B. et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat. Biotechnol. 30, 1210–1216 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Qiu, Y. et al. Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide. J. Control. Rel. 314, 102–115 (2019).

    Article  CAS  Google Scholar 

  93. Lou, B. et al. Preparation of mRNA polyplexes with post-conjugated endosome-disruptive peptides. Methods Mol. Biol. 2355, 275–286 (2021).

    Article  CAS  PubMed  Google Scholar 

  94. Yeom, J. H. et al. Inhibition of xenograft tumor growth by gold nanoparticle-DNA oligonucleotide conjugates-assisted delivery of BAX mRNA. PLoS One 8, 75369 (2013).

    Article  ADS  Google Scholar 

  95. Sun, P. et al. Transcellular delivery of messenger RNA payloads by a cationic supramolecular MOF platform. Chem. Commun. 54, 11304–11307 (2018).

    Article  CAS  Google Scholar 

  96. Tsai, S. J. et al. Exosome-mediated mRNA delivery in vivo is safe and can be used to induce SARS-CoV-2 immunity. J. Biol. Chem. 297, 101266 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhitnyuk, Y. et al. Efficient mRNA delivery system utilizing chimeric VSVG-L7Ae virus-like particles. Biochem. Biophys. Res. Commun. 505, 1097–1102 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Tacchi, L. et al. Nasal immunity is an ancient arm of the mucosal immune system of vertebrates. Nat. Commun. 5, 5205 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  99. Strugnell, R. A. & Wijburg, O. L. The role of secretory antibodies in infection immunity. Nat. Rev. Microbiol. 8, 656–667 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Jansen, E. M. et al. Are inhaled mRNA vaccines safe and effective? A review of preclinical studies. Expert. Opin. Drug. Deliv. 19, 1471–1485 (2022).

    Article  CAS  PubMed  Google Scholar 

  101. Mao, T. et al. Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses. Science 378, eabo2523 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hartwell, B. L. et al. Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity. Sci. Transl. Med. 14, eabn1413 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang, J. et al. Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity. Science 367, 869 (2020).

    Article  Google Scholar 

  104. Zheng, B. et al. Inhalable nanovaccine with biomimetic coronavirus structure to trigger mucosal immunity of respiratory tract against COVID-19. Chem. Eng. J. 418, 129392 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  105. Popowski, K. D. et al. Inhalable dry powder mRNA vaccines based on extracellular vesicles. Matter 5, 2960–2974 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bessa, J. et al. Efficient induction of mucosal and systemic immune responses by virus-like particles administered intranasally: implications for vaccine design. Eur. J. Immunol. 38, 114–126 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Koppolu, B. & Zaharoff, D. A. The effect of antigen encapsulation in chitosan particles on uptake, activation and presentation by antigen presenting cells. Biomaterials 34, 2359–2369 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Wilson, J. T. et al. Enhancement of MHC-I antigen presentation via architectural control of pH-responsive, endosomolytic polymer nanoparticles. AAPS J. 17, 358–369 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Xing, Y. et al. Synthesis of poly(acyclic orthoester)s: acid-sensitive biomaterials for enhancing immune responses of protein. Vaccine. Angew. Chem. Int. Edn. 59, 7235–7239 (2020).

    Article  CAS  Google Scholar 

  111. Cai, H. et al. Multivalent antigen presentation enhances the immunogenicity of a synthetic three-component HIV-1 V3 glycopeptide vaccine. ACS Cent. Sci. 4, 582–589 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang, F., Lu, Y. J. & Malley, R. Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity. Proc. Natl. Acad. Sci. USA 110, 13564–13569 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang, C. et al. Bioengineering of artificial antigen presenting cells and lymphoid organs. Theranostics 7, 3504–3516 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Steenblock, E. R. & Fahmy, T. M. A comprehensive platform for ex vivo T-cell expansion based on biodegradable polymeric artificial antigen-presenting cells. Mol. Ther. 16, 765–772 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Joshi, N., Walter, J. M. & Misharin, A. V. Alveolar macrophages. Cell. Immunol. 330, 86–90 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Allard, B., Panariti, A. & Martin, J. G. Alveolar macrophages in the resolution of inflammation, tissue repair, and tolerance to infection. Front. Immunol. 9, 1777 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Chuquimia, O. D. et al. The role of alveolar epithelial cells in initiating and shaping pulmonary immune responses: communication between innate and adaptive immune systems. PLoS One 7, e32125 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Quinton, L. J., Walkey, A. J. & Mizgerd, J. P. Integrative physiology of pneumonia. Physiol. Rev. 98, 1417–1464 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Muhammad, W., Zhai, Z., Wang, S. & Gao, C. Inflammation‐modulating nanoparticles for pneumonia therapy. Wiley Interdisc. Rev. Nanomed. Nanobiotechnol. 14, e1763 (2022).

    Article  CAS  Google Scholar 

  122. Ohbayashi, H. Matrix metalloproteinases in lung diseases. Curr. Protein Pept. Sci. 3, 409–421 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. van den Brand, J. M. A., Haagmans, B. L., van Riel, D., Osterhaus, A. D. M. E. & Kuiken, T. The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models. J. Comp. Pathol. 151, 83–112 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Wang, P. et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135 (2021).

    Article  ADS  CAS  PubMed  Google Scholar 

  125. Renn, A., Fu, Y., Hu, X., Hall, M. D. & Simeonov, A. Fruitful neutralizing antibody pipeline brings hope to defeat SARS-Cov-2. Trends Pharmacol. Sci. 41, 815–829 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jiang, D., Liang, J., Li, Y. & Noble, P. W. The role of Toll-like receptors in non-infectious lung injury. Cell Res. 16, 693–701 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Gao, W. et al. Size-dependent anti-inflammatory activity of a peptide-gold nanoparticle hybrid in vitro and in a mouse model of acute lung injury. Acta Biomater. 85, 203–217 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Okutani, D., Lodyga, M., Han, B. & Liu, M. Src protein tyrosine kinase family and acute inflammatory responses. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L129–L141 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Hanke, J. H. et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. J. Biol. Chem. 271, 695–701 (1996).

    Article  CAS  PubMed  Google Scholar 

  130. Fung, S.-Y. et al. The potential of nanoscale combinations of self-assembling peptides and amino acids of the Src tyrosine kinase inhibitor in acute lung injury therapy. Biomaterials 32, 4000–4008 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Zhang, C. Y. et al. pH-responsive nanoparticles targeted to lungs for improved therapy of acute lung inflammation/injury. ACS Appl. Mater. Interf. 11, 16380–16390 (2019).

    Article  CAS  Google Scholar 

  132. Lo Cicero, A., Stahl, P. D. & Raposo, G. Extracellular vesicles shuffling intercellular messages: for good or for bad. Curr. Opin. Cell Biol. 35, 69–77 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Inal, J. M. Decoy ACE2-expressing extracellular vesicles that competitively bind SARS-CoV-2 as a possible COVID-19 therapy. Clin. Sci. 134, 1301–1304 (2020).

    Article  CAS  Google Scholar 

  134. Xie, F. et al. Engineering extracellular vesicles enriched with palmitoylated ACE2 as COVID‐19 therapy. Adv. Mater. 33, 2103471 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Huang, X. et al. Nanotechnology-based strategies against SARS-CoV-2 variants. Nat. Nanotechnol. 17, 1027–1037 (2022).

    Article  ADS  CAS  PubMed  Google Scholar 

  136. Rao, L., Tian, R. & Chen, X. Cell-membrane-mimicking nanodecoys against infectious diseases. ACS Nano 14, 2569–2574 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang, C. et al. Membrane nanoparticles derived from ACE2-rich cells block SARS-CoV-2 infection. ACS Nano 15, 6340–6351 (2021).

    Article  CAS  PubMed  Google Scholar 

  138. Zhang, Q. et al. Cellular nanosponges inhibit SARS-CoV-2 infectivity. Nano Lett. 20, 5570–5574 (2020).

    Article  ADS  CAS  PubMed  Google Scholar 

  139. Lin, C. H., Chang, S. H. & Fang, J. Y. Recent advances using phosphodiesterase 4 (PDE4) inhibitors to treat inflammatory disorders: animal and clinical studies. Curr. Drug. Ther. 11, 21–40 (2016).

    Article  CAS  Google Scholar 

  140. Yu, H.-P. et al. Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency. J. Nanobiotechnol. 18, 25 (2020).

    Article  CAS  Google Scholar 

  141. Wang, Z., Li, J., Cho, J. & Malik, A. B. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nat. Nanotechnol. 9, 204–210 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  142. Okeke, E. B. et al. Inhibition of neutrophil elastase prevents neutrophil extracellular trap formation and rescues mice from endotoxic shock. Biomaterials 238, 119836 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Logie, C., Van Schaik, T., Pompe, T. & Pietsch, K. Fibronectin-functionalization of 3D collagen networks supports immune tolerance and inflammation suppression in human monocyte-derived macrophages. Biomaterials 268, 120498 (2021).

    Article  CAS  PubMed  Google Scholar 

  144. Yin, H., Fang, J., Liao, L., Nakamura, H. & Maeda, H. Styrene-maleic acid copolymer-encapsulated CORM2, a water-soluble carbon monoxide (CO) donor with a constant CO-releasing property, exhibits therapeutic potential for inflammatory bowel disease. J. Controlled Rel. 187, 14–21 (2014).

    Article  CAS  Google Scholar 

  145. Guo, J. et al. Cyclodextrin-derived intrinsically bioactive nanoparticles for treatment of acute and chronic inflammatory diseases. Adv. Mater. 31, 1904607 (2019).

    Article  CAS  Google Scholar 

  146. Rao, L. et al. Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines. Proc. Natl. Acad. Sci. USA 117, 27141–27147 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhang, H. et al. Inhalable nanocatchers for SARS-CoV-2 inhibition. Proc. Natl. Acad. Sci. USA 118, e2102957118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Li, Y. et al. Dual-mode nanoprobes for reactive oxygen species scavenging and treatment of acute lung injury. Appl. Surf. Sci. 610, 155458 (2023).

    Article  CAS  Google Scholar 

  149. Zhu, Y. et al. Porous Se@SiO2 nanospheres treated paraquat-induced acute lung injury by resisting oxidative stress. Int. J. Nanomed. 12, 7143–7152 (2017).

    Article  CAS  Google Scholar 

  150. Bhattacharjee, A., Basu, A., Biswas, J. & Bhattacharya, S. Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice. Mol. Cell. Biochem. 405, 243–256 (2015).

    Article  CAS  PubMed  Google Scholar 

  151. Zhou, Y. et al. Inhalable gadofullerenol/[70] fullerenol as high-efficiency ROS scavengers for pulmonary fibrosis therapy. Nanomed. Nanotechnol. Biol. Med. 14, 1361–1369 (2018).

    Article  CAS  Google Scholar 

  152. Li, L. et al. A broad-spectrum ROS-eliminating material for prevention of inflammation and drug-induced organ toxicity. Adv. Sci. 5, 1800781 (2018).

    Article  Google Scholar 

  153. Ji, H. et al. Inhaled pro-efferocytic nanozymes promote resolution of acute lung injury. Adv. Sci. 9, 2201696 (2022).

    Article  CAS  Google Scholar 

  154. Head, M. G., Brown, R. J., Newell, M. L., Scott, J. A. G., Batchelor, J. & Atun, R. The allocation of US$105 billion in global funding from G20 countries for infectious disease research between 2000 and 2017: a content analysis of investments. Lancet Glob. Health. 8, e1295–e1304 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Heida, R., Hinrichs, W. & Frijlink, H. Inhaled vaccine delivery in the combat against respiratory viruses: a 2021 overview of recent developments and implications for COVID-19. Expert. Rev. Vaccines 21, 957–974 (2022).

    Article  CAS  PubMed  Google Scholar 

  156. Li, J. X. et al. Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial. Lancet Respir. Med. 10, 739–748 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Saravolatz, L. D., Depcinski, S. & Sharma, M. Molnupiravir and nirmatrelvir-ritonavir: oral COVID antiviral drugs. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciac180 (2022).

    Article  Google Scholar 

  158. Fernandes, Q. et al. Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis, therapeutics and vaccines. Ann. Med. 54, 524–540 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Forgham, H., Kakinen, A., Qiao, R. & Davis, T. P. Keeping up with the COVIDs—could siRNA-based antivirals be a part of the answer? Exploration 2, 20220012 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  160. AminJafari, A. & Ghasemi, S. The possible of immunotherapy for COVID-19: a systematic review. Int. Immunopharmacol. 83, 106455 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wu, Q. et al. Evaluation of the safety profile of COVID-19 vaccines: a rapid review. BMC Med. 19, 173 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Schieffelin, J. S., Norton, E. B. & Kolls, J. K. What should define a SARS-CoV-2 “breakthrough” infection? J. Clin. Invest. 131, E151186 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Beatty, G. L. & Gladney, W. L. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 21, 687–692 (2015).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by the National Key Research and Development Program of China (grant numbers 2021YFA1201000, 2018YFE0117800, 2021YFC2302400 and 2021YFE0106900), the National Natural Science Foundation of China (NSFC) key project (grant number 32030060); the NSFC (grant numbers 31971302, 31871003 and 32171394), the NSFC international collaboration key project (grant number 51861135103), the Natural Science Foundation of Guangdong Province of China (grant number 2019A1515011597), and the joint grant between Guangzhou City and College (grant number 202102010106), The Beijing–Tianjin–Hebei Basic Research Cooperation Project (grant number 19JCZDJC64100) and the Educational Commission of Guangdong Province of China key project (grant number 2020ZDZX2001).

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Author notes

  1. These authors contributed equally: Yafang Xiao, Yuanyu Huang, Maobin Xie.

Authors and Affiliations

  1. Department of Minimally Invasive Interventional Radiology, the State Key Laboratory of Respiratory Disease, School of Biomedical Engineering & The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, P. R. China

    Yafang Xiao, Maobin Xie, Ying Tao, Jiasheng Wu, Guoxi Xie, Tao Xu, Weisheng Guo & Xing-Jie Liang

  2. Advanced Research Institute of Multidisciplinary Science, School of Life Science; School of Medical Technology; Key Laboratory of Molecular Medicine and Biotherapy; Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing, P. R. China

    Yuanyu Huang & Minghui Yang

  3. Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Safety, National Center for Nanoscience and Technology of China, Beijing, P.R. China

    Lu Liu & Xing-Jie Liang

  4. University of Chinese Academy of Sciences, Beijing, P. R. China

    Lu Liu, Tao Xu & Xing-Jie Liang

  5. State Key Laboratory of Respiratory Disease and School of Basic Medicine, Guangzhou Medical University, Guangzhou, P. R. China

    Jinbao Liu

  6. National Laboratory of Biomedicine at Guangzhou, Guangzhou, P. R. China

    Tao Xu

  7. Institute of Biophysics, Chinese Academy of Science, Beijing, P. R. China

    Tao Xu

  8. Department of Health Sciences, National Natural Science Foundation of China, Beijing, P. R. China

    Weisheng Guo

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Contributions

Y.X., Y.H. and M.X. contributed equally to the preparation of this manuscript. Y.X. and X.-J.L. contributed to writing and editing of this manuscript. Y.H., M.X. and X.-J.L. researched data for the article and contributed to the discussion of content and writing. M.Y., Y.T., L.L., J.W. and X.-J.L. researched data for the article. G.X., J.L. and T.X. contributed to reviewing and editing the manuscript. Y.H., W.G. and X.-J.L. contributed to the discussions and writing, reviewing and editing of the manuscript.

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Correspondence to Yuanyu Huang, Weisheng Guo or Xing-Jie Liang.

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Xiao, Y., Huang, Y., Xie, M. et al. Immunoregulatory nanomedicine for respiratory infections. Nat Rev Bioeng 2, 244–259 (2024). https://doi.org/10.1038/s44222-023-00131-8

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