Abstract
mRNA vaccines have emerged as a revolutionary tool to generate rapid and precise immune responses against infectious diseases and cancers. Compared with conventional vaccines such as inactivated viruses, viral vectors, protein subunits or DNA-based vaccines, mRNA vaccines stand out owing to multiple advantages, including simplicity of design, fast production, enhanced safety and high efficacy. Nevertheless, efficient and targeted delivery of mRNA molecules remains a significant challenge owing to their inherent instability and susceptibility to degradation. Nanotechnology offers innovative solutions to surmount these obstacles and amplify the potency of mRNA vaccines. This Primer aims to outline a modular approach to developing biomaterials and nanotechnology for mRNA vaccines, with a focus on particle design, formulation evaluation and therapeutic applications. We delve into the underlying mechanisms of nanoparticle-facilitated mRNA protection, cellular uptake, endosomal escape and immune stimulation. We underscore the critical parameters that impact the manufacturing and clinical implementation of nanomaterial-based mRNA vaccines. Finally, we present the current limitations and future perspectives in the advancement of nanotechnology-enhanced mRNA vaccines for broad applications in prophylactic and therapeutic interventions.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 1 digital issues and online access to articles
$119.00 per year
only $119.00 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021).
Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014).
Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). This article comprehensively details an overview of the immune mechanism and disease applications of mRNA vaccines.
Arevalo, C. P. et al. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science 378, 899–904 (2022).
Zhang, N. N. et al. A thermostable mRNA vaccine against COVID-19. Cell 182, 1271–1283 (2020).
Guo, M. et al. A lipid-based LMP2–mRNA vaccine to treat nasopharyngeal carcinoma. Nano Res. 16, 5357–5367 (2023).
Lorentzen, C. L., Haanen, J. B., Met, Ö. & Svane, I. M. Clinical advances and ongoing trials on mRNA vaccines for cancer treatment. Lancet Oncol. 23, e450–e458 (2022).
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).
Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).
Fang, E. et al. Advances in COVID-19 mRNA vaccine development. Signal Transduct. Target. Ther. 7, 94 (2022).
Lin, C. C. et al. Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation. Nat. Commun. 12, 3878 (2021).
Li, C. et al. Mechanisms of innate and adaptive immunity to the Pfizer–BioNTech BNT162b2 vaccine. Nat. Immunol. 23, 543–555 (2022). This study describes the potential mechanisms underlying the innate and adaptive immune responses elicited by BNT162b2.
Psarras, A., Wittmann, M. & Vital, E. M. Emerging concepts of type I interferons in SLE pathogenesis and therapy. Nat. Rev. Rheumatol. 18, 575–590 (2022).
Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).
Li, B., Luo, X. & Dong, Y. Effects of chemically modified messenger RNA on protein expression. Bioconjug. Chem. 27, 849–853 (2016).
Liu, J. et al. Developmental mRNA m(5)C landscape and regulatory innovations of massive m(5)C modification of maternal mRNAs in animals. Nat. Commun. 13, 2484 (2022).
Kormann, M. S. et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat. Biotechnol. 29, 154–157 (2011).
Zeng, C. et al. Leveraging mRNA sequences and nanoparticles to deliver SARS-CoV-2 antigens in vivo. Adv. Mater. 32, e2004452 (2020). This article describes an mRNA engineering strategy to augment generation of SARS-CoV-2 antigen proteins.
Huang, X. et al. The landscape of mRNA nanomedicine. Nat. Med. 28, 2273–2287 (2022). This article presents the latest advances and innovations in the growing field of mRNA nanomedicine.
Spencer, A. J. et al. Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice. Nat. Commun. 12, 2893 (2021).
Rappaport, A. R. et al. Low-dose self-amplifying mRNA COVID-19 vaccine drives strong protective immunity in non-human primates against SARS-CoV-2 infection. Nat. Commun. 13, 3289 (2022).
Cohen, J. First self-copying mRNA vaccine proves itself in pandemic trial. Science 376, 446 (2022).
Szubert, A. J. et al. COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2. eClinicalMedicine 56, 101823 (2023).
Leppek, K. et al. Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics. Nat. Commun. 13, 1536 (2022).
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021). This article outlines design principles of LNPs for mRNA delivery.
Krienke, C. et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021).
McMahon, M. et al. Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses. Proc. Natl Acad. Sci. USA 119, e2206333119 (2022). This article accesses a nucleoside-modified mRNA–LNP platform for influenza viruses.
Muramatsu, H. et al. Lyophilization provides long-term stability for a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine. Mol. Ther. 30, 1941–1951 (2022).
Huang, X. G. et al. Nanotechnology-based strategies against SARS-CoV-2 variants. Nat. Nanotechnol. 17, 1027–1037 (2022). This article provides nanotechnology solutions for dealing with SARS-CoV-2 variants.
Anderluzzi, G. et al. The role of nanoparticle format and route of administration on self-amplifying mRNA vaccine potency. J. Control. Release 342, 388–399 (2022).
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).
Tenchov, R., Bird, R., Curtze, A. E. & Zhou, Q. Lipid nanoparticles — from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano 15, 16982–17015 (2021).
Dilliard, S. A. & Siegwart, D. J. Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs. Nat. Rev. Mater. 8, 282–300 (2023).
Han, X. et al. An ionizable lipid toolbox for RNA delivery. Nat. Commun. 12, 7233 (2021).
Horejs, C. From lipids to lipid nanoparticles to mRNA vaccines. Nat. Rev. Mater. 6, 1075–1076 (2021).
Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021). This investigation presents a membrane-destabilizing ionizable phospholipid with multiple tails, facilitating selective mRNA transport and precise CRISPR–Cas9 gene manipulation within specific organs.
Xiao, Y. et al. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat. Commun. 13, 758 (2022).
Wang, X. et al. Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery. Nat. Protoc. 18, 265–291 (2023).
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).
Xiao, Y. et al. Emerging mRNA technologies: delivery strategies and biomedical applications. Chem. Soc. Rev. 51, 3828–3845 (2022). This review introduces the nano-delivery platforms of mRNA technology and its implementations in the field of biomedicine.
Zhang, Y., Sun, C., Wang, C., Jankovic, K. E. & Dong, Y. Lipids and lipid derivatives for RNA delivery. Chem. Rev. 121, 12181–12277 (2021). This review provides a comprehensive review on lipids or lipid-derived materials for RNA delivery.
Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020).
Kauffman, K. J. et al. Optimization of lipid nanoparticle formulations for mRNA delivery in vivo with fractional factorial and definitive screening designs. Nano Lett. 15, 7300–7306 (2015).
Koltover, I., Salditt, T., Rädler, J. O. & Safinya, C. R. An inverted hexagonal phase of cationic liposome–DNA complexes related to DNA release and delivery. Science 281, 78–81 (1998).
Patel, S. et al. Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA. Nat. Commun. 11, 983 (2020).
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).
Maeki, M., Uno, S., Niwa, A., Okada, Y. & Tokeshi, M. Microfluidic technologies and devices for lipid nanoparticle-based RNA delivery. J. Control. Release 344, 80–96 (2022).
Jahn, A., Vreeland, W. N., Gaitan, M. & Locascio, L. E. Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. J. Am. Chem. Soc. 126, 2674–2675 (2004).
Kulkarni, J. A. et al. Spontaneous, solvent-free entrapment of siRNA within lipid nanoparticles. Nanoscale 12, 23959–23966 (2020).
Shah, S., Dhawan, V., Holm, R., Nagarsenker, M. S. & Perrie, Y. Liposomes: advancements and innovation in the manufacturing process. Adv. Drug Deliv. Rev. 154-155, 102–122 (2020).
Yanez Arteta, M. et al. Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles. Proc. Natl Acad. Sci. USA 115, E3351–e3360 (2018).
Kulkarni, J. A. et al. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630–643 (2021).
Miao, L., Zhang, Y. & Huang, L. mRNA vaccine for cancer immunotherapy. Mol. Cancer 20, 41 (2021).
Ferhan, A. R. et al. Lipid nanoparticle technologies for nucleic acid delivery: a nanoarchitectonics perspective. Adv. Funct. Mater. 32, 2203669 (2022).
Malone, R. W., Felgner, P. L. & Verma, I. M. Cationic liposome-mediated RNA transfection. Proc. Natl Acad. Sci. USA 86, 6077–6081 (1989).
Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446–453 (2020).
Sasaki, K., Sato, Y., Okuda, K., Iwakawa, K. & Harashima, H. mRNA-loaded lipid nanoparticles targeting dendritic cells for cancer immunotherapy. Pharmaceutics 14, 1572 (2022).
Pollard, C. et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther. 21, 251–259 (2013).
Langer, R. & Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797–800 (1976).
Zhang, D. et al. One-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer delivery systems for mRNA. J. Am. Chem. Soc. 143, 12315–12327 (2021).
Abbasi, S. et al. Co-encapsulation of Cas9 mRNA and guide RNA in polyplex micelles enables genome editing in mouse brain. J. Control. Release 332, 260–268 (2021).
Siewert, C. et al. Investigation of charge ratio variation in mRNA — DEAE-dextran polyplex delivery systems. Biomaterials 192, 612–620 (2019).
Boussif, O. et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl Acad. Sci. USA 92, 7297–7301 (1995).
Schulze, J. et al. Spray-dried nanoparticle-in-microparticle delivery systems (NiMDS) for gene delivery, comprising polyethylenimine (PEI)-based nanoparticles in a poly(vinyl alcohol) matrix. Small 14, e1701810 (2018).
Liu, X. et al. Inhibition of hypoxia-induced proliferation of pulmonary arterial smooth muscle cells by a mTOR siRNA-loaded cyclodextrin nanovector. Biomaterials 35, 4401–4416 (2014).
Ke, X. et al. Surface-functionalized PEGylated nanoparticles deliver messenger RNA to pulmonary immune cells. ACS Appl. Mater. Interfaces 12, 35835–35844 (2020).
Li, M. et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J. Control. Release 228, 9–19 (2016).
Breunig, M. et al. Mechanistic investigation of poly(ethylene imine)-based siRNA delivery: disulfide bonds boost intracellular release of the cargo. J. Control. Release 130, 57–63 (2008).
Schroeder, A. et al. Alkane-modified short polyethyleneimine for siRNA delivery. J. Control. Release 160, 172–176 (2012).
Dahlman, J. E. et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nat. Nanotechnol. 9, 648–655 (2014).
Zhang, D. et al. Targeted delivery of mRNA with one-component ionizable amphiphilic Janus dendrimers. J. Am. Chem. Soc. 143, 17975–17982 (2021).
Lyu, Z. & Peng, L. Potent drugless dendrimers. Nat. Biomed. Eng. 1, 686–688 (2017).
Zhang, D. et al. The unexpected importance of the primary structure of the hydrophobic part of one-component ionizable amphiphilic Janus dendrimers in targeted mRNA delivery activity. J. Am. Chem. Soc. 144, 4746–4753 (2022).
Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E4133–E4142 (2016).
Zhang, D. et al. Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Nat. Nanotechnol. 17, 777–787 (2022). This study presents a novel approach for utilizing NP systems to treat tumours through gene editing.
Lu, Y. et al. Micelles with ultralow critical micelle concentration as carriers for drug delivery. Nat. Biomed. Eng. 2, 318–325 (2018).
Cabral, H., Miyata, K., Osada, K. & Kataoka, K. Block copolymer micelles in nanomedicine applications. Chem. Rev. 118, 6844–6892 (2018).
Prieve, M. G. et al. Targeted mRNA therapy for ornithine transcarbamylase deficiency. Mol. Ther. 26, 801–813 (2018).
Ren, J. et al. Self-assembled polymeric micelle as a novel mRNA delivery carrier. J. Control. Release 338, 537–547 (2021).
Koji, K. et al. Bundling of mRNA strands inside polyion complexes improves mRNA delivery efficiency in vitro and in vivo. Biomaterials 261, 120332 (2020).
Miyazaki, T. et al. Polymeric nanocarriers with controlled chain flexibility boost mRNA delivery in vivo through enhanced structural fastening. Adv. Healthc. Mater. 9, e2000538 (2020).
Yoshinaga, N. et al. Bridging mRNA and polycation using RNA oligonucleotide derivatives improves the robustness of polyplex micelles for efficient mRNA delivery. Adv. Healthc. Mater. 11, e2102016 (2022).
Uchida, S. et al. Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety. Biomaterials 82, 221–228 (2016).
Haabeth, O. A. 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). This study describes a strategy to use charge-altering releasable transporters to deliver mRNA in vivo to treat tumours.
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, E448–E456 (2017).
McKinlay, C. J., Benner, N. L., Haabeth, O. A., Waymouth, R. M. & Wender, P. A. Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters. Proc. Natl Acad. Sci. USA 115, E5859–E5866 (2018).
Blakney, A. K. et al. Big is beautiful: enhanced saRNA delivery and immunogenicity by a higher molecular weight, bioreducible, cationic polymer. ACS Nano 14, 5711–5727 (2020).
Jaiswal, M., Dudhe, R. & Sharma, P. K. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech 5, 123–127 (2015).
Gupta, A., Eral, H. B., Hatton, T. A. & Doyle, P. S. Nanoemulsions: formation, properties and applications. Soft Matter 12, 2826–2841 (2016).
Zhang, W. et al. Lipid carriers for mRNA delivery. Acta Pharmaceut. Sin. B https://doi.org/10.1016/j.apsb.2022.11.026 (2022).
Tsai, T. F. Fluad®-MF59®-adjuvanted influenza vaccine in older adults. Infect. Chemother. 45, 159–174 (2013).
Brito, L. A. et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol. Ther. 22, 2118–2129 (2014).
Bogers, W. M. et al. Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion. J. Infect. Dis. 211, 947–955 (2014).
Samsa, M. M. et al. Self-amplifying RNA vaccines for Venezuelan equine encephalitis virus induce robust protective immunogenicity in mice. Mol. Ther. 27, 850–865 (2019).
Stokes, A. et al. Nonclinical safety assessment of repeated administration and biodistribution of a novel rabies self-amplifying mRNA vaccine in rats. Regul. Toxicol. Pharmacol. 113, 104648 (2020).
Luisi, K. et al. Development of a potent Zika virus vaccine using self-amplifying messenger RNA. Sci. Adv. 6, eaba5068 (2020).
Erasmus, J. H. et al. An alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates. Sci. Transl. Med. 12, eabc9396 (2020).
Kanekiyo, M. et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499, 102–106 (2013).
Song, N. et al. Ferritin: a multifunctional nanoplatform for biological detection, imaging diagnosis, and drug delivery. Acc. Chem. Res. 54, 3313–3325 (2021).
Zhang, J. et al. Cargo loading within ferritin nanocages in preparation for tumor-targeted delivery. Nat. Protoc. 16, 4878–4896 (2021).
Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol. 40, 840–854 (2022). This article describes the translational advancements of mRNA-based vaccines and immunotherapeutic modalities in clinical settings.
Yadav, M., Atala, A. & Lu, B. Developing all-in-one virus-like particles for Cas9 mRNA/single guide RNA co-delivery and aptamer-containing lentiviral vectors for improved gene expression. Int. J. Biol. Macromol. 209, 1260–1270 (2022).
Kallen, K. J. et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive(®) vaccines. Hum. Vaccin. Immunother. 9, 2263–2276 (2013).
Kübler, H. et al. Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study. J. Immunother. Cancer 3, 26 (2015).
Gebre, M. S. et al. Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine. Nature 601, 410–414 (2022). This report presents the findings of a study comparing the immunogenicity and protective efficacy of CVnCoV and CV2CoV.
Geng, J. et al. Emerging landscape of cell-penetrating peptide-mediated nucleic acid delivery and their utility in imaging, gene-editing, and RNA-sequencing. J. Control. Release 341, 166–183 (2022).
Udhayakumar, V. K. et al. Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide. Adv. Healthc. Mater. 6, 1601412 (2017).
Coolen, A. L. et al. Poly(lactic acid) nanoparticles and cell-penetrating peptide potentiate mRNA-based vaccine expression in dendritic cells triggering their activation. Biomaterials 195, 23–37 (2019).
Oude Egberink, R. et al. Biomaterial-mediated protein expression induced by peptide–mRNA nanoparticles embedded in lyophilized collagen scaffolds. Pharmaceutics 14, 1619 (2022).
Gurumurthy, C. B., Quadros, R. M. & Ohtsuka, M. Prototype mouse models for researching SEND-based mRNA delivery and gene therapy. Nat. Protoc. 17, 2129–2138 (2022).
Mohsen, M. O., Zha, L., Cabral-Miranda, G. & Bachmann, M. F. Major findings and recent advances in virus-like particle (VLP)-based vaccines. Semin. Immunol. 34, 123–132 (2017).
Li, J. et al. Messenger RNA vaccine based on recombinant MS2 virus-like particles against prostate cancer. Int. J. Cancer 134, 1683–1694 (2014).
Zhitnyuk, Y. et al. Efficient mRNA delivery system utilizing chimeric VSVG-L7Ae virus-like particles. Biochem. Biophys. Res. Commun. 505, 1097–1102 (2018).
Jain, A., Singh, S. K., Arya, S. K., Kundu, S. C. & Kapoor, S. Protein nanoparticles: promising platforms for drug delivery applications. ACS Biomater. Sci. Eng. 4, 3939–3961 (2018).
Zhong, Y., Du, S. & Dong, Y. mRNA delivery in cancer immunotherapy. Acta Pharmaceut. Sin. B 13, 1348–1357 (2023).
Xue, Y. et al. Recent advances in biomaterial-boosted adoptive cell therapy. Chem. Soc. Rev. 51, 1766–1794 (2022).
Goddard, Z. R., Marín, M. J., Russell, D. A. & Searcey, M. Active targeting of gold nanoparticles as cancer therapeutics. Chem. Soc. Rev. 49, 8774–8789 (2020).
Yeom, J. H. et al. Inhibition of Xenograft tumor growth by gold nanoparticle–DNA oligonucleotide conjugates-assisted delivery of BAX mRNA. PLoS ONE 8, e75369 (2013).
Liu, Q. et al. Mesoporous silica-coated silver nanoparticles as ciprofloxacin/siRNA carriers for accelerated infected wound healing. J. Nanobiotechnol. 20, 386 (2022).
Yuan, P. et al. Intracellular co-delivery of native antibody and siRNA for combination therapy by using biodegradable silica nanocapsules. Biomaterials 281, 121376 (2022).
Torney, F., Trewyn, B. G., Lin, V. S. & Wang, K. Mesoporous silica nanoparticles deliver DNA and chemicals into plants. Nat. Nanotechnol. 2, 295–300 (2007).
Zhang, W., Liu, Y., Min Chin, J. & Phua, K. K. L. Sustained release of PKR inhibitor C16 from mesoporous silica nanoparticles significantly enhances mRNA translation and anti-tumor vaccination. Eur. J. Pharm. Biopharm. 163, 179–187 (2021).
Liu, Y. et al. A novel graphene quantum dot-based mRNA delivery platform. ChemistryOpen 10, 666–671 (2021).
Yang, Z. et al. Superparamagnetic iron oxide nanoparticles modified with polyethylenimine and galactose for siRNA targeted delivery in hepatocellular carcinoma therapy. Int. J. Nanomed. 13, 1851–1865 (2018).
Zeng, C., Zhang, C., Walker, P. G. & Dong, Y. Formulation and delivery technologies for mRNA vaccines. Curr. Top. Microbiol. Immunol. 440, 71–110 (2022).
Renu, S. et al. Poly(I:C) augments inactivated influenza virus-chitosan nanovaccine induced cell mediated immune response in pigs vaccinated intranasally. Vet. Microbiol. 242, 108611 (2020).
Roier, S. et al. Intranasal immunization with nontypeable Haemophilus influenzae outer membrane vesicles induces cross-protective immunity in mice. PLoS ONE 7, e42664 (2012).
Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 217, 345–351 (2015).
Mangadlao, J. D. et al. Prostate-specific membrane antigen targeted gold nanoparticles for theranostics of prostate cancer. ACS Nano 12, 3714–3725 (2018).
Marbella, L. E. et al. Description and role of bimetallic prenucleation species in the formation of small nanoparticle alloys. J. Am. Chem. Soc. 137, 15852–15858 (2015).
Modena, M. M., Rühle, B., Burg, T. P. & Wuttke, S. Nanoparticle characterization: what to measure? Adv. Mater. 31, e1901556 (2019).
Koolen, C. D. et al. High-throughput sizing, counting, and elemental analysis of anisotropic multimetallic nanoparticles with single-particle inductively coupled plasma mass spectrometry. ACS Nano 16, 11968–11978 (2022).
Ward-O’Brien, B. et al. Quantum confined high-entropy lanthanide oxysulfide colloidal nanocrystals. Nano Lett. 22, 8045–8051 (2022).
Frey, H., Beck, A., Huang, X., van Bokhoven, J. A. & Willinger, M. G. Dynamic interplay between metal nanoparticles and oxide support under redox conditions. Science 376, 982–987 (2022).
Daneshvar, M. & Hosseini, M. R. From the iron boring scraps to superparamagnetic nanoparticles through an aerobic biological route. J. Hazard. Mater. 357, 393–400 (2018).
Canton, I. & Battaglia, G. Endocytosis at the nanoscale. Chem. Soc. Rev. 41, 2718–2739 (2012).
Zhao, Z., Ukidve, A., Krishnan, V. & Mitragotri, S. Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers. Adv. Drug Deliv. Rev. 143, 3–21 (2019).
Yu, M. et al. Temperature- and rigidity-mediated rapid transport of lipid nanovesicles in hydrogels. Proc. Natl Acad. Sci. USA 116, 5362–5369 (2019).
Huang, X., Teng, X., Chen, D., Tang, F. & He, J. The effect of the shape of mesoporous silica nanoparticles on cellular uptake and cell function. Biomaterials 31, 438–448 (2010).
Reifarth, M., Hoeppener, S. & Schubert, U. S. Uptake and intracellular fate of engineered nanoparticles in mammalian cells: capabilities and limitations of transmission electron microscopy-polymer-based nanoparticles. Adv. Mater. 30, 1703704 (2018).
Quesada-González, D. et al. Signal enhancement on gold nanoparticle-based lateral flow tests using cellulose nanofibers. Biosens. Bioelectron. 141, 111407 (2019).
Suresh, D., Suresh, A. & Kannan, R. Engineering biomolecular systems: controlling the self-assembly of gelatin to form ultra-small bioactive nanomaterials. Bioact. Mater. 18, 321–336 (2022).
Swingle, K. L. et al. Amniotic fluid stabilized lipid nanoparticles for in utero intra-amniotic mRNA delivery. J. Control. Release 341, 616–633 (2022).
Li, J. et al. Interfacial properties and micellization of triblock poly(ethylene glycol)-poly(ε-caprolactone)-polyethyleneimine copolymers. Acta Pharm. Sin. B 10, 1122–1133 (2020).
Fischer, K. & Schmidt, M. Pitfalls and novel applications of particle sizing by dynamic light scattering. Biomaterials 98, 79–91 (2016).
Sitar, S. et al. Pitfalls in size characterization of soft particles by dynamic light scattering online coupled to asymmetrical flow field-flow fractionation. Anal. Chem. 89, 11744–11752 (2017).
Doane, T. L., Chuang, C. H., Hill, R. J. & Burda, C. Nanoparticle ζ-potentials. Acc. Chem. Res. 45, 317–326 (2012).
Woo, H. K. et al. Characterization and modulation of surface charges to enhance extracellular vesicle isolation in plasma. Theranostics 12, 1988–1998 (2022).
Roach, L. et al. Evaluating phospholipid-functionalized gold nanorods for in vivo applications. Small 17, e2006797 (2021).
Soyluoglu, M., Kim, D., Zaker, Y. & Karanfil, T. Stability of oxygen nanobubbles under freshwater conditions. Water Res. 206, 117749 (2021).
Shlar, I. et al. High-throughput screening of nanoparticle-stabilizing ligands: application to preparing antimicrobial curcumin nanoparticles by antisolvent precipitation. Nanomicro Lett. 7, 68–79 (2015).
Rajamohan, N. & Al Shibli, F. Synthesis and application of carbon substrate nano material from biomass for surface protection — effect of variables, electrochemical and isotherm studies. Chemosphere 292, 133479 (2022).
Hu, B. et al. Engineering surface patterns on nanoparticles: new insights into nano–bio interactions. J. Mater. Chem. B 10, 2357–2383 (2022).
Zhao, X. et al. Oxidative stress- and mitochondrial dysfunction-mediated cytotoxicity by silica nanoparticle in lung epithelial cells from metabolomic perspective. Chemosphere 275, 129969 (2021).
Xia, T. et al. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano 2, 2121–2134 (2008).
Liu, L. et al. Negative regulation of cationic nanoparticle-induced inflammatory toxicity through the increased production of prostaglandin E2 via mitochondrial DNA-activated Ly6C(+) monocytes. Theranostics 8, 3138–3152 (2018).
Setyawati, M. I., Tay, C. Y. & Leong, D. T. Mechanistic investigation of the biological effects of SiO2, TiO2, and ZnO nanoparticles on intestinal cells. Small 11, 3458–3468 (2015).
Park, J. D. et al. Lobar evenness of deposition/retention in rat lungs of inhaled silver nanoparticles: an approach for reducing animal use while maximizing endpoints. Part. Fibre Toxicol. 16, 2 (2019).
Kim, H. P. et al. Even lobar deposition of poorly soluble gold nanoparticles (AuNPs) is similar to that of soluble silver nanoparticles (AgNPs). Part. Fibre Toxicol. 17, 54 (2020).
Qi, Y. et al. Silica nanoparticles induce cardiac injury and dysfunction via ROS/Ca(2+)/CaMKII signaling. Sci. Total Environ. 837, 155733 (2022).
Morimoto, Y., Horie, M., Kobayashi, N., Shinohara, N. & Shimada, M. Inhalation toxicity assessment of carbon-based nanoparticles. Acc. Chem. Res. 46, 770–781 (2013).
Adamcakova-Dodd, A. et al. Toxicity assessment of zinc oxide nanoparticles using sub-acute and sub-chronic murine inhalation models. Part. Fibre Toxicol. 11, 15 (2014).
Andreozzi, P. et al. Novel core–shell polyamine phosphate nanoparticles self-assembled from PEGylated poly(allylamine hydrochloride) with low toxicity and increased in vivo circulation time. Small 17, e2102211 (2021).
Yoshida, M., Roh, K. H. & Lahann, J. Short-term biocompatibility of biphasic nanocolloids with potential use as anisotropic imaging probes. Biomaterials 28, 2446–2456 (2007).
Zhu, C. et al. Rational administration sequencing of immunochemotherapy elicits powerful anti-tumor effect. J. Control. Release 341, 769–781 (2022).
Muddana, H. S., Morgan, T. T., Adair, J. H. & Butler, P. J. Photophysics of Cy3-encapsulated calcium phosphate nanoparticles. Nano Lett. 9, 1559–1566 (2009).
Sobska, J. et al. Counterion-insulated near-infrared dyes in biodegradable polymer nanoparticles for in vivo imaging. Nanoscale Adv. 4, 39–48 (2021).
Zhukova, V. et al. Fluorescently labeled PLGA nanoparticles for visualization in vitro and in vivo: the importance of dye properties. Pharmaceutics 13, 1145 (2021).
Carrasco, M. J. et al. Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration. Commun. Biol. 4, 956 (2021).
Goswami, R., O’Hagan, D. T., Adamo, R. & Baudner, B. C. Conjugation of mannans to enhance the potency of liposome nanoparticles for the delivery of RNA vaccines. Pharmaceutics 13, 240 (2021).
Naderi Sohi, A. et al. Development of an mRNA-LNP vaccine against SARS-CoV-2: evaluation of immune response in mouse and rhesus macaque. Vaccines 9, 1007 (2021).
Chen, Z. et al. A polyphenol-assisted IL-10 mRNA delivery system for ulcerative colitis. Acta Pharm. Sin. B 12, 3367–3382 (2022).
Berk, A. J. & Sharp, P. A. Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell 12, 721–732 (1977).
Schüttpelz, M. et al. Changes in conformational dynamics of mRNA upon AtGRP7 binding studied by fluorescence correlation spectroscopy. J. Am. Chem. Soc. 130, 9507–9513 (2008).
Packer, M., Gyawali, D., Yerabolu, R., Schariter, J. & White, P. A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems. Nat. Commun. 12, 6777 (2021). This article demonstrates the mechanism behind mRNA activity loss in LNP delivery owing to electrophilic impurities from ionizable cationic lipids.
Kubista, M. et al. The real-time polymerase chain reaction. Mol. Aspects Med. 27, 95–125 (2006).
Li, B. et al. An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo. Nano Lett. 15, 8099–8107 (2015).
Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019).
Kong, N. et al. Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer. Proc. Natl Acad. Sci. USA 119, e2112696119 (2022). This study reports a method for the delivery of KDM6A mRNA using mucosal NPs for the treatment of bladder cancer.
Kong, N. et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Sci. Transl. Med. 11, eaaw1565 (2019).
Lin, Y. X. et al. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci. Transl. Med. 13, eaba9772 (2021).
Cagigi, A. & Loré, K. Immune responses induced by mRNA vaccination in mice, monkeys and humans. Vaccines 9, 61 (2021).
Deng, Y. Q. et al. Lipid nanoparticle-encapsulated mRNA antibody provides long-term protection against SARS-CoV-2 in mice and hamsters. Cell Res. 32, 375–382 (2022).
Alameh, M. G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54, 2877–2892.e7 (2021).
Laczkó, D. et al. A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity 53, 724–732.e7 (2020).
Sawaki, D. et al. Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production. Circulation 138, 809–822 (2018).
Armstrong, H. K. et al. Unfermented β-fructan fibers fuel inflammation in select inflammatory bowel disease patients. Gastroenterology 164, 228–240 (2023).
Islam, M. A. et al. Adjuvant-pulsed mRNA vaccine nanoparticle for immunoprophylactic and therapeutic tumor suppression in mice. Biomaterials 266, 120431 (2021).
Chen, G. L. et al. Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Microbe 3, e193–e202 (2022). This study reports a clinical trial on the safety and immunogenicity of the ARCoV mRNA vaccine.
Mileto, D. et al. SARS-CoV-2 mRNA vaccine BNT162b2 triggers a consistent cross-variant humoral and cellular response. Emerg. Microbes Infect. 10, 2235–2243 (2021).
Chen, Y. et al. Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses. Nat. Rev. Immunol. 23, 189–199 (2022).
Chen, K. et al. mRNA vaccines against SARS-CoV-2 variants delivered by lipid nanoparticles based on novel ionizable lipids. Adv. Funct. Mater. 32, 2204692 (2022).
Sun, W. et al. The self-assembled nanoparticle-based trimeric RBD mRNA vaccine elicits robust and durable protective immunity against SARS-CoV-2 in mice. Signal Transduct. Target. Ther. 6, 340 (2021).
Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). To our knowledge, this study reports for the first time the metagenomic RNA sequence of SARS-CoV-2.
Dickerman, B. A. et al. Comparative effectiveness of BNT162b2 and mRNA-1273 vaccines in U.S. veterans. N. Engl. J. Med. 386, 105–115 (2022).
Verbeke, R., Lentacker, I., De Smedt, S. C. & Dewitte, H. The dawn of mRNA vaccines: the COVID-19 case. J. Control. Release 333, 511–520 (2021).
Basha, G. et al. Influence of cationic lipid composition on gene silencing properties of lipid nanoparticle formulations of siRNA in antigen-presenting cells. Mol. Ther. 19, 2186–2200 (2011).
Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653–658 (2013).
Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R. & Blankschtein, D. mRNA vaccine delivery using lipid nanoparticles. Ther. Deliv. 7, 319–334 (2016).
Risma, K. A. et al. Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines. J. Allergy Clin. Immunol. 147, 2075–2082 (2021).
Banerji, A. et al. mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: current evidence and suggested approach. J. Allergy Clin. Immunol. Pract. 9, 1423–1437 (2021).
Cabanillas, B., Akdis, C. A. & Novak, N. Allergic reactions to the first COVID-19 vaccine: a potential role of polyethylene glycol? Allergy 76, 1617–1618 (2021).
Li, J. et al. Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study. Nat. Med. 27, 1062–1070 (2021).
Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).
Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).
Lin, D. Y. et al. Effectiveness of bivalent boosters against severe omicron infection. N. Engl. J. Med. 388, 764–766 (2023). This study reports the effectiveness of bivalent vaccines against Omicron infection.
Ng, K. W. et al. SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies. Sci. Transl. Med. 14, eabn3715 (2022).
Wang, Y. et al. Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies. Cell Discov. 8, 104 (2022). This article presents a bispecific antibody-based strategy against SARS-CoV-2 variants.
Zhang, L. et al. Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants. Nat. Chem. Biol. 18, 342–351 (2022).
Awasthi, S. et al. Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models. J. Clin. Invest. 131, e152310 (2021).
Freyn, A. W. et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol. Ther. 28, 1569–1584 (2020).
Corey, L. et al. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N. Engl. J. Med. 384, 1003–1014 (2021).
Mallory, K. L. et al. Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice. npj Vaccines 6, 84 (2021).
Aldrich, C. et al. Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: a phase 1 trial. Vaccine 39, 1310–1318 (2021).
Meyer, M. et al. Modified mRNA-based vaccines elicit robust immune responses and protect guinea pigs from Ebola virus disease. J. Infect. Dis. 217, 451–455 (2018).
Pardi, N. et al. Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques. Mol. Ther. Nucleic Acids 15, 36–47 (2019).
August, A. et al. A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against chikungunya virus. Nat. Med. 27, 2224–2233 (2021).
Hewitt, S. L. et al. Intratumoral IL12 mRNA therapy promotes TH1 transformation of the tumor microenvironment. Clin. Cancer Res. 26, 6284–6298 (2020).
Liu, L. et al. Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer. Mol. Ther. 26, 45–55 (2018).
Liu, C. et al. mRNA-based cancer therapeutics. Nat. Rev. Cancer https://doi.org/10.1038/s41568-023-00586-2 (2023). This review presents recent advances in mRNA technology for cancer therapy.
Huang, X., Tang, T., Zhang, G. & Liang, T. Identification of tumor antigens and immune subtypes of cholangiocarcinoma for mRNA vaccine development. Mol. Cancer. 20, 50 (2021).
Huang, X., Zhang, G., Tang, T. Y., Gao, X. & Liang, T. B. Personalized pancreatic cancer therapy: from the perspective of mRNA vaccine. Mil. Med. Res. 9, 53 (2022).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
No authors listed. mRNA vaccine slows melanoma recurrence. Cancer Discov. 13, 1278 (2023).
Wei, J. & Hui, A. M. The paradigm shift in treatment from Covid-19 to oncology with mRNA vaccines. Cancer Treat. Rev. 107, 102405 (2022).
Porciuncula, A. et al. Spatial mapping and immunomodulatory role of the OX40/OX40L pathway in human non-small cell lung cancer. Clin. Cancer Res. 27, 6174–6183 (2021).
Patel, M. R. et al. A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. J. Clin. Oncol. 38, 3092–3092 (2020).
Abadier, M. et al. 708 MEDI1191 (IL-12 mRNA) induces peripheral and intratumoral immunostimulatory effect in patients with cutaneous or subcutaneous (C/SC) lesions. J. Immunother. Cancer 10, A741 (2022).
Li, T. et al. Current progress in the development of prophylactic and therapeutic vaccines. Sci. China Life Sci. 66, 679–710 (2023).
Abdelzaher, H. M. et al. RNA vaccines against infectious diseases: vital progress with room for improvement. Vaccines 9, 1211 (2021).
Heine, A., Juranek, S. & Brossart, P. Clinical and immunological effects of mRNA vaccines in malignant diseases. Mol. Cancer 20, 52 (2021).
Yarchoan, M., Johnson, B. A. III, Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017).
Nawaz, M. et al. Lipid nanoparticles deliver the therapeutic VEGFA mRNA in vitro and in vivo and transform extracellular vesicles for their functional extensions. Adv. Sci. 10, e2206187 (2023).
Suk, J. S., Xu, Q., Kim, N., Hanes, J. & Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28–51 (2016).
Kong, L., Campbell, F. & Kros, A. DePEGylation strategies to increase cancer nanomedicine efficacy. Nanoscale Horiz. 4, 378–387 (2019).
Rizvi, F. et al. Murine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA. Nat. Commun. 12, 613 (2021).
Jiang, L. et al. Systemic messenger RNA as an etiological treatment for acute intermittent porphyria. Nat. Med. 24, 1899–1909 (2018).
Schrom, E. et al. Translation of angiotensin-converting enzyme 2 upon liver- and lung-targeted delivery of optimized chemically modified mRNA. Mol. Ther. Nucleic Acids 7, 350–365 (2017).
Qiu, M. et al. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of ANGPTL3. Proc. Natl Acad. Sci. USA 118, e2020401118 (2021).
Gan, Z. et al. Nanoparticles containing constrained phospholipids deliver mRNA to liver immune cells in vivo without targeting ligands. Bioeng. Transl. Med. 5, e10161 (2020).
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).
Ogawa, K. et al. Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain. J. Control. Release 348, 34–41 (2022).
Rui, Y., Wilson, D. R. & Green, J. J. Non-viral delivery to enable genome editing. Trends Biotechnol. 37, 281–293 (2019).
Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).
Bhattacharyya, T., Dasgupta, A. K., Ray, N. R. & Sarkar, S. Molecular discriminators using single wall carbon nanotubes. Nanotechnology 23, 385304 (2012).
Larson, N. R. et al. pH-dependent phase behavior and stability of cationic lipid–mRNA nanoparticles. J. Pharm. Sci. 111, 690–698 (2022).
Kobiyama, K. & Ishii, K. J. Making innate sense of mRNA vaccine adjuvanticity. Nat. Immunol. 23, 474–476 (2022).
Tahtinen, S. et al. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat. Immunol. 23, 532–542 (2022).
Kim, B. et al. Optimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines. J. Control. Release 353, 241–253 (2023).
Zhao, P. et al. Long-term storage of lipid-like nanoparticles for mRNA delivery. Bioact. Mater. 5, 358–363 (2020).
Jones, K. L., Drane, D. & Gowans, E. J. Long-term storage of DNA-free RNA for use in vaccine studies. Biotechniques 43, 675–681 (2007).
Vander Straeten, A. et al. A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-01774-z (2023).
Alberer, M. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 390, 1511–1520 (2017).
Shimabukuro, T. & Nair, N. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer–BioNTech Covid-19 vaccine. J. Am. Med. Assoc. 325, 780–781 (2021).
Chu, D. K. et al. Risk of second allergic reaction to SARS-CoV-2 vaccines: a systematic review and meta-analysis. JAMA Intern. Med. 182, 376–385 (2022).
Castells, M. C. & Phillips, E. J. Maintaining safety with SARS-CoV-2 vaccines. N. Engl. J. Med. 384, 643–649 (2021).
Ju, Y. et al. Impact of anti-PEG antibodies induced by SARS-CoV-2 mRNA vaccines. Nat. Rev. Immunol. 23, 135–136 (2023).
Ermilova, I. & Swenson, J. DOPC versus DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA. Phys. Chem. Chem. Phys. 22, 28256–28268 (2020).
Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018).
Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).
Hayashi, C. T. H. et al. mRNA-LNP expressing PfCSP and Pfs25 vaccine candidates targeting infection and transmission of Plasmodium falciparum. npj Vaccines 7, 155 (2022).
Baeza Garcia, A. et al. Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection. Nat. Commun. 9, 2714 (2018).
Sajid, A. et al. mRNA vaccination induces tick resistance and prevents transmission of the Lyme disease agent. Sci. Transl. Med. 13, eabj9827 (2021).
Duthie, M. S. et al. Heterologous immunization with defined RNA and subunit vaccines enhances T cell responses that protect against Leishmania donovani. Front. Immunol. 9, 2420 (2018).
Xue, T. et al. RNA encoding the MPT83 antigen induces protective immune responses against Mycobacterium tuberculosis infection. Infect. Immun. 72, 6324–6329 (2004).
Kon, E. et al. A single-dose F1-based mRNA–LNP vaccine provides protection against the lethal plague bacterium. Sci. Adv. 9, eadg1036 (2023).
Perez-Garcia, C. G. et al. Development of an mRNA replacement therapy for phenylketonuria. Mol. Ther. Nucleic Acids 28, 87–98 (2022).
You, Y. et al. Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-022-00989-w (2023).
Acknowledgements
The authors acknowledge the support from the American Heart Association (AHA) Transformational Project Award (23TPA1072337; W.T.), AHA’s Second Century Early Faculty Independence Award (23SCEFIA1151841; W.T.), American Lung Association (ALA) Cancer Discovery Award (LCD1034625; W.T.), ALA Courtney Cox Cole Lung Cancer Research Award (No. 2022A017206; W.T.), Novo Nordisk ValidatioNN Award (No. 2023A009607; W.T.), Harvard/Brigham Health & Technology Innovation Fund (No. 2023A004452; W.T.), Department of Anesthesiology-Basic Scientist Grant (No. 2420 BPA075; W.T.), Nanotechnology Foundation (No. 2022A002721; W.T.), Gillian Reny Stepping Strong Center for Trauma Innovation Breakthrough Innovator Award (No. 113548; W.T.), Khoury Innovation Award (No. 2020A003219; W.T.), Center for Nanomedicine Research Fund (No. 2019A014810; W.T.), National Institute of Allergy and Infectious Diseases (No. R01AI174902; Y.D.), National Institute of General Medical Sciences (No. R35GM144117; Y.D.), the National Institutes of Health (R01 EB025192-01A1 and R01 CA269787-01; D.J.S.) and Farokhzad Family Distinguished Chair Foundation (No. 018129; W.T.).
Author information
Authors and Affiliations
Contributions
Introduction (S.C., X.H., Y.X. and E.Á.-B.); Experimentation (S.C., X.H., Y.X. and E.Á.-B.); Results (S.C., X.H. and Y.X.); Applications (S.C., X.H., Y.X. and E.Á.-B.); Reproducibility and data deposition (S.C. and E.Á.-B.); Limitations and optimizations (S.C., X.H., Y.X., Y.S., W.C. and S.K.); Outlook (S.C., X.H., E.Á.-B. and W.C.); and overview of the Primer (D.J.S., Y.D. and W.T.).
Corresponding authors
Ethics declarations
Competing interests
D.J.S. declares the following competing interests: ReCode Therapeutics, Tome Biosciences, Signify Bio, and Pfizer Inc. Y.D. is a scientific advisory board member of Oncorus Inc., Arbor Biotechnologies, and FL85. The other authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Methods Primers thanks Anna Blakney, Dan Peer, Joseph Rosenecker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Clearance rate
-
The volume or quantity of a substance removed from a system per unit of time.
- Encapsulation efficiency
-
The proportion of mRNA molecules successfully enclosed within the nanoparticle carrier.
- Self-amplifying mRNA vaccines
-
mRNA vaccines incorporate engineered mRNA sequences to perpetually generate specific antigens, thereby augmenting and extending the immune response.
- Zeta potential
-
The electrokinetic potential difference between the dispersing medium and the immobile layer of fluid adhered to the dispersed particle, reflecting the surface charge and potential interactions.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Chen, S., Huang, X., Xue, Y. et al. Nanotechnology-based mRNA vaccines. Nat Rev Methods Primers 3, 63 (2023). https://doi.org/10.1038/s43586-023-00246-7
Accepted:
Published:
DOI: https://doi.org/10.1038/s43586-023-00246-7
This article is cited by
-
The quest for nanoparticle-powered vaccines in cancer immunotherapy
Journal of Nanobiotechnology (2024)
-
LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing
Nature Communications (2024)
-
Engineering nanomaterials for glioblastoma nanovaccination
Nature Reviews Materials (2024)
-
Therapeutic nucleic acids in regenerative medicine and tissue repair
Nano Research (2024)
-
Facile green synthesis of lanthanum oxide nanoparticles: their photocatalytic and electrochemical applications
Journal of Materials Science: Materials in Electronics (2024)