Skip to main content

Advertisement

SpringerLink
Log in

RNA Nanomedicine: Delivery Strategies and Applications

  • Review Article-theme
  • Recent Advances in Drug Delivery
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Delivery of RNA using nanomaterials has emerged as a new modality to expand therapeutic applications in biomedical research. However, the delivery of RNA presents unique challenges due to its susceptibility to degradation and the requirement for efficient intracellular delivery. The integration of nanotechnologies with RNA delivery has addressed many of these challenges. In this review, we discuss different strategies employed in the design and development of nanomaterials for RNA delivery. We also highlight recent advances in the pharmaceutical applications of RNA delivered via nanomaterials. Various nanomaterials, such as lipids, polymers, peptides, nucleic acids, and inorganic nanomaterials, have been utilized for delivering functional RNAs, including messenger RNA (mRNA), small interfering RNA, single guide RNA, and microRNA. Furthermore, the utilization of nanomaterials has expanded the applications of functional RNA as active pharmaceutical ingredients. For instance, the delivery of antigen-encoding mRNA using nanomaterials enables the transient expression of vaccine antigens, leading to immunogenicity and prevention against infectious diseases. Additionally, nanomaterial-mediated RNA delivery has been investigated for engineering cells to express exogenous functional proteins. Nanomaterials have also been employed for co-delivering single guide RNA and mRNA to facilitate gene editing of genetic diseases. Apart from the progress made in RNA medicine, we discuss the current challenges and future directions in this field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Barbier AJ, Jiang AY, Zhang P, Wooster R, Anderson DG. The clinical progress of mRNA vaccines and immunotherapies. Nat Biotechnol. 2022;40(6):840–54.

    CAS  PubMed  Google Scholar 

  2. Esrick EB, Lehmann LE, Biffi A, Achebe M, Brendel C, Ciuculescu MF, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205–15.

    CAS  PubMed  Google Scholar 

  3. Wang C, Zhang Y, Dong Y. Lipid nanoparticle-mRNA formulations for therapeutic applications. Acc Chem Res. 2021;54(23):4283–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sabnis S, Kumarasinghe ES, Salerno T, Mihai C, Ketova T, Senn JJ, et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol Ther. 2018;26(6):1509–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Frangoul H, Altshuler D, Cappellini D, Chen YS, Domm J, Eustace BK, et al. CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassemia. N Engl J Med. 2021;384(23): e91.

    PubMed  Google Scholar 

  6. Nguyen GN, Everett JK, Kafle S, Roche AM, Raymond HE, Leiby J, et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat Biotechnol. 2021;39(1):47–55.

    CAS  PubMed  Google Scholar 

  7. Corbett KS, Edwards DK, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. 2020;586(7830):567–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bloom K, van den Berg F, Arbuthnot P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther. 2021;28(3–4):117–29.

    CAS  PubMed  Google Scholar 

  9. Rappaport AR, Hong SJ, Scallan CD, Gitlin L, Akoopie A, Boucher GR, 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. 2022;13(1):3289.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Anderluzzi G, Lou G, Woods S, Schmidt ST, Gallorini S, Brazzoli M, et al. The role of nanoparticle format and route of administration on self-amplifying mRNA vaccine potency. J Control Release. 2022;342:388–99.

    CAS  PubMed  Google Scholar 

  11. Blakney AK, McKay PF, Hu K, Samnuan K, Jain N, Brown A, et al. Polymeric and lipid nanoparticles for delivery of self-amplifying RNA vaccines. J Control Release. 2021;338:201–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19(10):673–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021;6(12):1078–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Jung HN, Lee SY, Lee S, Youn H, Im HJ. Lipid nanoparticles for delivery of RNA therapeutics: current status and the role of in vivo imaging. Theranostics. 2022;12(17):7509–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Riley RS, Kashyap MV, Billingsley MM, White B, Alameh MG, Bose SK, et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci Adv. 2021;7(3):eaba1028.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Billingsley MM, Singh N, Ravikumar P, Zhang R, June CH, Mitchell MJ. Ionizable lipid nanoparticle-mediated mRNA delivery for human CAR T cell engineering. Nano Lett. 2020;20(3):1578–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20(6):359–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim J, Jozic A, Lin YX, Eygeris Y, Bloom E, Tan XC, et al. Engineering lipid nanoparticles for enhanced intracellular delivery of mRNA through inhalation. ACS Nano. 2022;16(9):14792–806.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cortez-Jugo C, Qi AS, Rajapaksa A, Friend JR, Yeo LY. Pulmonary monoclonal antibody delivery via a portable microfluidic nebulization platform. Biomicrofluidics. 2015;9(5): 052603.

    PubMed  PubMed Central  Google Scholar 

  20. Mo Y, Cheng MHY, D’Elia A, Doran K, Ding L, Chen J, et al. Light-activated siRNA endosomal release (LASER) by porphyrin lipid nanoparticles. ACS Nano. 2023;17(5):4688–703.

    CAS  PubMed  Google Scholar 

  21. Massiot J, Rosilio V, Ibrahim N, Yamamoto A, Nicolas V, Konovalov O, et al. Newly synthesized lipid-porphyrin conjugates: evaluation of their self-assembling properties, their miscibility with phospholipids and their photodynamic activity in vitro. Chem-Eur J. 2018;24(72):19179–94.

    CAS  PubMed  Google Scholar 

  22. Fabozzi A, Della Sala F, di Gennaro M, Barretta M, Longobardo G, Solimando N, et al. Design of functional nanoparticles by microfluidic platforms as advanced drug delivery systems for cancer therapy. Lab Chip. 2023;23(5):1389–409.

    CAS  PubMed  Google Scholar 

  23. Rotolo L, Vanover D, Bruno NC, Peck HE, Zurla C, Murray J, et al. Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung. Nat Mater. 2023;22(3):369–79.

    CAS  PubMed  Google Scholar 

  24. Sun YZ, Davis E. Nanoplatforms for targeted stimuli-responsive drug delivery: a review of platform materials and stimuli-responsive release and targeting mechanisms. Nanomaterials. 2021;11(3):746.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20(2):101–24.

    CAS  PubMed  Google Scholar 

  26. Huang J, Zhuang C, Chen J, Chen X, Li X, Zhang T, et al. Targeted drug/gene/photodynamic therapy via a stimuli-responsive dendritic-polymer-based nanococktail for treatment of EGFR-TKI-resistant non-small-cell lung cancer. Adv Mater. 2022;34(27): e2201516.

    PubMed  Google Scholar 

  27. Rudolph C, Ortiz A, Schillinger U, Jauernig J, Plank C, Rosenecker J. Methodological optimization of polyethylenimine (PEI)-based gene delivery to the lungs of mice via aerosol application. J Gene Med. 2005;7(1):59–66.

    CAS  PubMed  Google Scholar 

  28. McLachlan G, Davidson H, Holder E, Davies LA, Pringle IA, Sumner-Jones SG, et al. Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung. Gene Ther. 2011;18(10):996–1005.

    CAS  PubMed  Google Scholar 

  29. Jiang Z, Cui W, Mager J, Thayumanavan S. Postfunctionalization of noncationic RNA-polymer complexes for RNA delivery. Ind Eng Chem Res. 2019;58(17):6982–91.

    CAS  Google Scholar 

  30. Boisguerin P, Konate K, Josse E, Vives E, Deshayes S. Peptide-based nanoparticles for therapeutic nucleic acid delivery. Biomedicines. 2021;9(5):583.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jia N, Ma J, Gao Y, Hu H, Chen D, Zhao X, et al. HA-modified R8-based bola-amphiphile nanocomplexes for effective improvement of siRNA delivery efficiency. ACS Biomater Sci Eng. 2020;6(4):2084–93.

    CAS  PubMed  Google Scholar 

  32. Wang H, Liu N, Yang F, Hu N, Wang M, Cui M, et al. Bioengineered protein nanocage by small heat shock proteins delivering mTERT siRNA for enhanced colorectal cancer suppression. ACS Appl Bio Mater. 2022;5(3):1330–40.

    CAS  PubMed  Google Scholar 

  33. Lang J, Zhao X, Qi Y, Zhang Y, Han X, Ding Y, et al. Reshaping prostate tumor microenvironment to suppress metastasis via cancer-associated fibroblast inactivation with peptide-assembly-based nanosystem. ACS Nano. 2019;13(11):12357–71.

    CAS  PubMed  Google Scholar 

  34. Zhang R, Tang L, Zhao B, Tian Y, Zhou B, Mu Y, et al. A peptide-based small RNA delivery system to suppress tumor growth by remodeling the tumor microenvironment. Mol Pharm. 2021;18(3):1431–43.

    CAS  PubMed  Google Scholar 

  35. Johnson MB, Chandler M, Afonin KA. Nucleic acid nanoparticles (NANPs) as molecular tools to direct desirable and avoid undesirable immunological effects. Adv Drug Deliver Rev. 2021;173:427–38.

    CAS  Google Scholar 

  36. Wu Y, Li Q, Shim G, Oh YK. Melanin-loaded CpG DNA hydrogel for modulation of tumor immune microenvironment. J Control Release. 2021;330:540–53.

    CAS  PubMed  Google Scholar 

  37. Le QV, Lee J, Byun J, Shim G, Oh YK. DNA-based artificial dendritic cells for in situ cytotoxic T cell stimulation and immunotherapy. Bioact Mater. 2022;15:160–72.

    CAS  PubMed  Google Scholar 

  38. Gao Y, Chen X, Tian T, Zhang T, Gao S, Zhang X, et al. A lysosome-activated tetrahedral nanobox for encapsulated siRNA delivery. Adv Mater. 2022;34(46): e2201731.

    PubMed  Google Scholar 

  39. Li S, Liu Y, Zhang T, Lin S, Shi S, He J, et al. A tetrahedral framework DNA-based bioswitchable miRNA inhibitor delivery system: application to skin anti-aging. Adv Mater. 2022;34(46): e2204287.

    PubMed  Google Scholar 

  40. Tian T, Zhao C, Li S, Huang Z, Guo Y, Dai W, et al. Liver-targeted delivery of small interfering RNA of C-C chemokine receptor 2 with tetrahedral framework nucleic acid attenuates liver cirrhosis. ACS Appl Mater Interfaces. 2023;15(8):10492–505.

    CAS  PubMed  Google Scholar 

  41. Luo C, Xie YQ, He MZ, Li YZ, Xia YH, He L, et al. Artificial nucleobase-directed programmable synthesis and assembly of amphiphilic nucleic acids as an all-in-one platform for cation-free siRNA delivery. Acs Appl Mater Inter. 2022;14(9):44019–28.

    CAS  Google Scholar 

  42. Maurizi E, Martella DA, Schiroli D, Merra A, Mustfa SA, Pellegrini G, et al. Nanoneedles induce targeted siRNA silencing of p16 in the human corneal endothelium. Adv Sci. 2022;9(33): e2203257.

    Google Scholar 

  43. Kang MA, Fang JS, Paragodaarachchi A, Kodama K, Yakobashvi D, Ichiyanagi Y, et al. Magnetically induced brownian motion of iron oxide nanocages in alternating magnetic fields and their application for efficient siRNA delivery. Nano Lett. 2022;22(22):8852–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zou Z, He L, Deng X, Wang H, Huang Z, Xue Q, et al. Zn(2+) -coordination-driven RNA assembly with retained integrity and biological functions. Angew Chem Int Ed Engl. 2021;60(42):22970–6.

    CAS  PubMed  Google Scholar 

  45. Mezghrani B, Ali LMA, Richeter S, Durand JO, Hesemann P, Bettache N. Periodic mesoporous ionosilica nanoparticles for green light photodynamic therapy and photochemical internalization of siRNA. ACS Appl Mater Interfaces. 2021;13(25):29325–39.

    CAS  PubMed  Google Scholar 

  46. Cheng Q, Wei T, Farbiak L, Johnson LT, Dilliard SA, Siegwart DJ. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat Nanotechnol. 2020;15(4):313–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li B, Manan RS, Liang SQ, Gordon A, Jiang AL, Varley A, et al. Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing. Nat Biotechnol. 2023; https://doi.org/10.1038/s41587-023-01679-x.

  48. Patel SK, Billingsley MM, Frazee C, Han X, Swingle KL, Qin J, et al. Hydroxycholesterol substitution in ionizable lipid nanoparticles for mRNA delivery to T cells. J Control Release. 2022;347:521–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hou X, Zhang X, Zhao W, Zeng C, Deng B, McComb DW, et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat Nanotechnol. 2020;15(1):41–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Li W, Zhang X, Zhang C, Yan J, Hou X, Du S, et al. Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy. Nat Commun. 2021;12(1):7264.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu S, Cheng Q, Wei T, Yu X, Johnson LT, Farbiak L, et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing. Nat Mater. 2021;20(5):701–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shi D, Toyonaga S, Anderson DG. In vivo RNA delivery to hematopoietic stem and progenitor cells via targeted lipid nanoparticles. Nano Lett. 2023;23(7):2938–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Rurik JG, Tombacz I, Yadegari A, Mendez Fernandez PO, Shewale SV, Li L, et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022;375(6576):91–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Han X, Gong N, Xue L, Billingsley M, El-Mayta R, Shepherd S, et al. Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis. Nat Commun. 2023;14(1):75.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Xue C, Hu SY, Gao ZH, Wang L, Luo MX, Yu X, et al. Programmably tiling rigidified DNA brick on gold nanoparticle as multi-functional shell for cancer-targeted delivery of siRNAs. Nat Commun. 2021;12(1):2928.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kim B, Sun S, Varner JA, Howell SB, Ruoslahti E, Sailor MJ. Securing the payload, finding the cell, and avoiding the endosome: peptide-targeted, fusogenic porous silicon nanoparticles for delivery of siRNA. Adv Mater. 2019;31(35):1902952.

    Google Scholar 

  57. Popowski KD, Moatti A, Scull G, Silkstone D, Lutz H, Lopez de Juan Abad B, et al. Inhalable dry powder mRNA vaccines based on extracellular vesicles. Matter. 2022;5(9):2960–74.

  58. Van Hoeck J, Van de Vyver T, Harizaj A, Goetgeluk G, Merckx P, Liu J, et al. Hydrogel-induced cell membrane disruptions enable direct cytosolic delivery of membrane-impermeable cargo. Adv Mater. 2021;33(30):2008054.

    Google Scholar 

  59. Chen Y, Zhao R, Li L, Zhao Y. Upconversion luminescence-boosted escape of DNAzyme from endosomes for enhanced gene-silencing efficacy. Angew Chem Int Ed Engl. 2022;61(34): e202206485.

    CAS  PubMed  Google Scholar 

  60. Chen R, Wang SK, Belk JA, Amaya L, Li Z, Cardenas A, et al. Engineering circular RNA for enhanced protein production. Nat Biotechnol. 2023;41(2):262–72.

    CAS  PubMed  Google Scholar 

  61. Harizaj A, Wels M, Raes L, Stremersch S, Goetgeluk G, Brans T, et al. Photoporation with biodegradable polydopamine nanosensitizers enables safe and efficient delivery of mRNA in human T cells. Adv Funct Mater. 2021;31(28):2102472.

    CAS  Google Scholar 

  62. Raes L, Pille M, Harizaj A, Goetgeluk G, Van Hoeck J, Stremersch S, et al. Cas9 RNP transfection by vapor nanobubble photoporation for ex vivo cell engineering. Mol Ther Nucleic Acids. 2021;25:696–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Fraire JC, Houthaeve G, Liu J, Raes L, Vermeulen L, Stremersch S, et al. Vapor nanobubble is the more reliable photothermal mechanism for inducing endosomal escape of siRNA without disturbing cell homeostasis. J Control Release. 2020;319:262–75.

    CAS  PubMed  Google Scholar 

  64. Li B, Zhao M, Lai W, Zhang X, Yang B, Chen X, et al. Activatable NIR-II photothermal lipid nanoparticles for improved messenger RNA delivery. Angew Chem Int Edit. 2023;62: e202302676.

    CAS  Google Scholar 

  65. Yue D, Cai XJ, Fan MN, Zhu JW, Tian J, Wu LH, et al. An alternating irradiation strategy-driven combination therapy of PDT and RNAi for highly efficient inhibition of tumor growth and metastasis. Adv Healthc Mater. 2021;10(8):2001850.

    CAS  Google Scholar 

  66. Lokugamage MP, Gan Z, Zurla C, Levin J, Islam FZ, Kalathoor S, et al. Mild innate immune activation overrides efficient nanoparticle-mediated RNA delivery. Adv Mater. 2020;32(1): e1904905.

    PubMed  Google Scholar 

  67. Van de Vyver T, De Smedt SC, Raemdonck K. Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics. Adv Drug Deliv Rev. 2022;181: 114041.

    PubMed  Google Scholar 

  68. Kim B, Hosn RR, Remba T, Yun D, Li N, Abraham W, et al. Optimization of storage conditions for lipid nanoparticle-formulated self-replicating RNA vaccines. J Control Release. 2023;353:241–53.

    CAS  PubMed  Google Scholar 

  69. Rhym LH, Manan RS, Koller A, Stephanie G, Anderson DG. Peptide-encoding mRNA barcodes for the high-throughput in vivo screening of libraries of lipid nanoparticles for mRNA delivery. Nat Biomed Eng. 2023;7(7):901–10.

    CAS  PubMed  Google Scholar 

  70. Wang W, Feng S, Ye Z, Gao H, Lin J, Ouyang D. Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm. Acta Pharm Sin B. 2022;12(6):2950–62.

    CAS  PubMed  Google Scholar 

  71. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11–21.

    CAS  PubMed  Google Scholar 

  72. Patel AK, Kaczmarek JC, Bose S, Kauffman KJ, Mir F, Heartlein MW, et al. Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium. Adv Mater. 2019;31(8): e1805116.

    PubMed  PubMed Central  Google Scholar 

  73. Zhu R, Hou M, Zhou Y, Ye H, Chen L, Ge CL, et al. Spherical alpha-helical polypeptide-mediated E2F1 silencing against myocardial ischemia-reperfusion injury (MIRI). Biomater Sci. 2022;10(21):6258–66.

    CAS  PubMed  Google Scholar 

  74. Chen L, Li G, Wang X, Li J, Zhang Y. Spherical nucleic acids for near-infrared light-responsive self-delivery of small-interfering RNA and antisense oligonucleotide. ACS Nano. 2021;15(7):11929–39.

    CAS  PubMed  Google Scholar 

  75. Liu J, Lu X, Wu T, Wu X, Han L, Ding B. Branched antisense and siRNA co-assembled nanoplatform for combined gene silencing and tumor therapy. Angew Chem Int Ed Engl. 2021;60(4):1853–60.

    CAS  PubMed  Google Scholar 

  76. Conde J, Ambrosone A, Hernandez Y, Tian FR, McCully M, Berry CC, et al. 15 years on siRNA delivery: beyond the state-of-the-Art on inorganic nanoparticles for RNAi therapeutics. Nano Today. 2015;10(4):421–50.

    CAS  Google Scholar 

  77. Slowing II, Vivero-Escoto JL, Wu CW, Lin VSY. Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Deliver Rev. 2008;60(11):1278–88.

    CAS  Google Scholar 

  78. Ho D, Sun X, Sun S. Monodisperse magnetic nanoparticles for theranostic applications. Acc Chem Res. 2011;44(10):875–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22(2):96–118.

    CAS  PubMed  Google Scholar 

  80. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Dong Y, Siegwart DJ, Anderson DG. Strategies, design, and chemistry in siRNA delivery systems. Adv Drug Deliv Rev. 2019;144:133–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kulkarni JA, Witzigmann D, Thomson SB, Chen S, Leavitt BR, Cullis PR, et al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol. 2021;16(6):630–43.

    CAS  PubMed  Google Scholar 

  83. Mui BL, Tam YK, Jayaraman M, Ansell SM, Du X, Tam YY, et al. Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles. Mol Ther Nucleic Acids. 2013;2(12): e139.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen J, Ye Z, Huang C, Qiu M, Song D, Li Y, et al. Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response. Proc Natl Acad Sci. 2022;119(34): e2207841119.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li Y, Ma X, Yue Y, Zhang K, Cheng K, Feng Q, et al. Rapid surface display of mRNA antigens by bacteria-derived outer membrane vesicles for a personalized tumor vaccine. Adv Mater. 2022;34(20): e2109984.

    PubMed  Google Scholar 

  86. Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021;371(6525):145–53.

    CAS  PubMed  Google Scholar 

  87. Larson RC, Maus MV. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 2021;21(3):145–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24(10):1499–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573(7774):430–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Mass E, Nimmerjahn F, Kierdorf K, Schlitzer A. Tissue-specific macrophages: How they develop and choreograph tissue biology. Nat Rev Immunol. 2023;23(9):563–79.

  91. Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38(8):947–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ye Z, Chen J, Zhao X, Li Y, Harmon J, Huang C, et al. In vitro engineering chimeric antigen receptor macrophages and T cells by lipid nanoparticle-mediated mRNA delivery. ACS Biomater Sci Eng. 2022;8(2):722–33.

    CAS  PubMed  Google Scholar 

  93. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. O’Brien K, Breyne K, Ughetto S, Laurent LC, Breakefield XO. RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat Rev Mol Cell Biol. 2020;21(10):585–606.

    PubMed  PubMed Central  Google Scholar 

  95. Yang Z, Shi J, Xie J, Wang Y, Sun J, Liu T, et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat Biomed Eng. 2020;4(1):69–83.

    CAS  PubMed  Google Scholar 

  96. Wang HX, Li M, Lee CM, Chakraborty S, Kim HW, Bao G, et al. CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery. Chem Rev. 2017;117(15):9874–906.

    CAS  PubMed  Google Scholar 

  97. Kenjo E, Hozumi H, Makita Y, Iwabuchi KA, Fujimoto N, Matsumoto S, et al. Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice. Nat Commun. 2021;12(1):7101.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Peters R, Harris T. Advances and innovations in haemophilia treatment. Nat Rev Drug Discov. 2018;17(7):493–508.

    CAS  PubMed  Google Scholar 

  99. Han JP, Kim M, Choi BS, Lee JH, Lee GS, Jeong M, et al. In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy. Sci Adv. 2022;8(3):eabj6901.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Qiu M, Glass Z, Chen J, Haas M, Jin X, Zhao X, 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. 2021;118(10): e2020401118.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Yang T, Poenisch M, Khanal R, Hu Q, Dai Z, Li R, et al. Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model. J Hepatol. 2021;75(6):1420–33.

    CAS  PubMed  Google Scholar 

  102. Ji W, Li Y, Peng H, Zhao R, Shen J, Wu Y, et al. Self-catalytic small interfering RNA nanocarriers for synergistic treatment of neurodegenerative diseases. Adv Mater. 2022;34(1): e2105711.

    PubMed  Google Scholar 

  103. Yang X, Yang W, Xia X, Lei T, Yang Z, Jia W, et al. Intranasal delivery of BACE1 siRNA and rapamycin by dual targets modified nanoparticles for Alzheimer’s disease therapy. Small. 2022;18(30): e2203182.

    PubMed  Google Scholar 

  104. Zhou Y, Zhu F, Liu Y, Zheng M, Wang Y, Zhang D, et al. Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer’s disease therapy. Sci Adv. 2020;6(41):eabc7031.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Li L, Long J, Sang Y, Wang X, Zhou X, Pan Y, et al. Rational preparation and application of a mRNA delivery system with cytidinyl/cationic lipid. J Control Release. 2021;340:114–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Andretto V, Repellin M, Pujol M, Almouazen E, Sidi-Boumedine J, Granjon T, et al. Hybrid core-shell particles for mRNA systemic delivery. J Control Release. 2023;353:1037–49.

    CAS  PubMed  Google Scholar 

  107. Linares-Fernandez S, Lacroix C, Exposito JY, Verrier B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol Med. 2020;26(3):311–23.

    CAS  PubMed  Google Scholar 

  108. Hashiba K, Sato Y, Taguchi M, Sakamoto S, Otsu A, Maeda Y, et al. Branching ionizable lipids can enhance the stability, fusogenicity, and functional delivery of mRNA. Small Sci. 2023;3(1):202200071.

    Google Scholar 

  109. Badieyan ZS, Berezhanskyy T, Utzinger M, Aneja MK, Emrich D, Erben R, et al. Transcript-activated collagen matrix as sustained mRNA delivery system for bone regeneration. J Control Release. 2016;239:137–48.

    CAS  PubMed  Google Scholar 

  110. Jiang T, Henderson JM, Coote K, Cheng Y, Valley HC, Zhang XO, et al. Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope. Nat Commun. 2020;11(1):1979.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kong N, Tao W, Ling X, Wang J, Xiao Y, Shi S, et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Sci Transl Med. 2019;11(523):eaaw1565.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Lee J, Kim D, Byun J, Wu Y, Park J, Oh YK. In vivo fate and intracellular trafficking of vaccine delivery systems. Adv Drug Deliv Rev. 2022;186: 114325.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ho T, Guidolin K, Makky A, Valic M, Ding L, Bu J, et al. Novel strategy to drive the intracellular uptake of lipid nanoparticles for photodynamic therapy. Angew Chem Int Ed Engl. 2023;62(16): e202218218.

    CAS  PubMed  Google Scholar 

  114. Zhao W, Zeng C, Yan J, Du S, Hou X, Zhang C, et al. Construction of messenger RNA (mRNA) probes delivered by lipid nanoparticles to visualize intracellular protein expression and localization at organelles. Adv Mater. 2021;33(45):2103131.

    CAS  Google Scholar 

  115. Jackson NAC, Kester KE, Casimiro D, Gurunathan S, DeRosa F. The promise of mRNA vaccines: a biotech and industrial perspective. NPJ Vaccines. 2020;5:11.

    PubMed  PubMed Central  Google Scholar 

  116. Liu Y, Yang G, Hui Y, Ranaweera S, Zhao CX. Microfluidic nanoparticles for drug delivery. Small. 2022;18(36): e2106580.

    PubMed  Google Scholar 

  117. Hasanzadeh A, Hamblin MR, Kiani J, Noori H, Hardie JM, Karimi M, et al. Could artificial intelligence revolutionize the development of nanovectors for gene therapy and mRNA vaccines? Nano Today. 2022;47: 101665.

    CAS  PubMed  Google Scholar 

Download references

Funding

This research was funded by grants from the National Research Foundation, Ministry of Science and ICT, Republic of Korea (NRF-2018R1A5A2024425; NRF-2021K2A9A2A06037695; NRF-2022M3E5F1017919); and from the Alchemist Project of the Korea Evaluation Institute of Industrial Technology (KEIT 20018560, NTIS 1415184668), the Ministry of Trade, Industry & Energy, Republic of Korea.

Author information

Author notes

  1. Junho Byun, Yina Wu, and Jinwon Park contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    Junho Byun, Yina Wu, Jinwon Park, Jung Suk Kim, Qiaoyun Li, Jaehyun Choi, Namjo Shin, Jaiwoo Lee & Yu-Kyoung Oh

  2. College of Pharmacy, Jinan University, Guangzhou, 510632, China

    Meng Lan & Yu Cai

Authors
  1. Junho Byun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yina Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinwon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jung Suk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiaoyun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jaehyun Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Namjo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Meng Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jaiwoo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yu-Kyoung Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JB: concept and design, and writing the manuscript; YW: concept and design, and writing the manuscript; JP: concept and design, and writing the manuscript; JSK: writing the manuscript; QL: writing the manuscript; JC: writing the manuscript; NS: writing the manuscript; JL: concept and design, writing the manuscript, and supervision; YKO: concept and design, writing the manuscript, manuscript review, supervision, and approval for version to be published. All authors contributed to the revision.

Corresponding authors

Correspondence to Jaiwoo Lee or Yu-Kyoung Oh.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Communicated by Aliasger Salem.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Byun, J., Wu, Y., Park, J. et al. RNA Nanomedicine: Delivery Strategies and Applications. AAPS J 25, 95 (2023). https://doi.org/10.1208/s12248-023-00860-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-023-00860-z

Keywords

Search

Navigation