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Nanocarrier-Mediated Delivery of MicroRNAs for Fibrotic Diseases

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Abstract

MicroRNAs (miRNAs) are endogenous noncoding RNAs that mediate the fibrotic process by regulating multiple targets. MicroRNA-based therapy can restore or inhibit miRNA expression and is expected to become an effective approach to prevent and alleviate fibrotic diseases. However, the safe, targeted, and effective delivery of miRNAs is a major challenge in translating miRNA therapy from bench to bedside. In this review, we briefly describe the pathophysiological process of fibrosis and the mechanism by which miRNAs regulate the progression of fibrosis. Additionally, we summarize the miRNA nanodelivery tools for fibrotic diseases, including chemical modifications and polymer-based, lipid-based, and exosome-based delivery systems. Further clarification of the role of miRNAs in fibrosis and the development of a novel nanodelivery system may facilitate the prevention and alleviation of fibrotic diseases in the future.

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References

  1. Rosenbloom J, Castro SV, Jimenez SA. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med. 2010;152(3):159–66.

    Article  PubMed  Google Scholar 

  2. Gerarduzzi C, Di Battista JA. Myofibroblast repair mechanisms post-inflammatory response: a fibrotic perspective. Inflamm Res. 2017;66(6):451–65.

    Article  CAS  PubMed  Google Scholar 

  3. Cvjeticanin B, Prutki M, Dumic-Cule I, Veir Z, Grgurevic L, Vukicevic S. Possible target for preventing fibrotic scar formation following acute myocardial infarction. Med Hypotheses. 2014;83(6):656–8.

    Article  CAS  PubMed  Google Scholar 

  4. Song K, Li Q, Yin XY, Lu Y, Liu CF, Hu LF. Hydrogen sulfide: a therapeutic candidate for fibrotic disease? Oxid Med Cell Longev. 2015;2015: 458720.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lemoinne S, Friedman SL. New and emerging anti-fibrotic therapeutics entering or already in clinical trials in chronic liver diseases. Curr Opin Pharmacol. 2019;49:60–70.

    Article  CAS  PubMed  Google Scholar 

  6. Zhao Y, Shi J, Lyu L. Critical role and potential therapeutic efficacy of interleukin-37 in the pathogenesis of keloid scarring. J Cosmet Dermatol. 2020;19(7):1805–6.

    Article  PubMed  Google Scholar 

  7. Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol. 2020;101:87–103.

    Article  PubMed  Google Scholar 

  8. Ulukan B, SilaOzkaya Y, Zeybel M. Advances in the epigenetics of fibroblast biology and fibrotic diseases. Curr Opin Pharmacol. 2019;49:102–9.

    Article  CAS  PubMed  Google Scholar 

  9. Kranick JC, Chadalavada DM, Sahu D, Showalter SA. Engineering double-stranded RNA binding activity into the Drosha double-stranded RNA binding domain results in a loss of microRNA processing function. PLoS One. 2017;12(8): e0182445.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lee D, Shin C. Emerging roles of DROSHA beyond primary microRNA processing. RNA Biol. 2018;15(2):186–93.

    Article  CAS  PubMed  Google Scholar 

  11. McGeary SE, Lin KS, Shi CY, Pham TM, Bisaria N, Kelley GM, et al. The biochemical basis of microRNA targeting efficacy. Science. 2019;366(6472): eaav1741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brummer A, Hausser J. MicroRNA binding sites in the coding region of mRNAs: extending the repertoire of post-transcriptional gene regulation. BioEssays. 2014;36(6):617–26.

    Article  PubMed  Google Scholar 

  13. Hausser J, Syed AP, Bilen B, Zavolan M. Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation. Genome Res. 2013;23(4):604–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fang Z, Rajewsky N. The impact of miRNA target sites in coding sequences and in 3’UTRs. PLoS One. 2011;6(3): e18067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xie M, Li M, Vilborg A, Lee N, Shu MD, Yartseva V, et al. Mammalian 5′-capped microRNA precursors that generate a single microRNA. Cell. 2013;155(7):1568–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang Z, Ma Z, Castillo-Gonzalez C, Sun D, Li Y, Yu B, et al. SWI2/SNF2 ATPase CHR2 remodels pri-miRNAs via Serrate to impede miRNA production. Nature. 2018;557(7706):516–21.

    Article  CAS  PubMed  Google Scholar 

  17. He Y, Deng Z, Alghamdi M, Lu L, Fear MW, He L. From genetics to epigenetics: new insights into keloid scarring. Cell Prolif. 2017;50(2): e12326.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Shi J, Yao S, Chen P, Yang Y, Qian M, Han Y, et al. The integrative regulatory network of circRNA and microRNA in keloid scarring. Mol Biol Rep. 2020;47(1):201–9.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang J, Xu D, Li N, Li Y, He Y, Hu X, et al. Downregulation of microRNA-31 inhibits proliferation and induces apoptosis by targeting HIF1AN in human keloid. Oncotarget. 2017;8(43):74623–34.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wolska-Gawron K, Bartosinska J, Krasowska D. MicroRNA in localized scleroderma: a review of literature. Arch Dermatol Res. 2020;312(5):317–24.

    Article  CAS  PubMed  Google Scholar 

  21. Gabisonia K, Prosdocimo G, Aquaro GD, Carlucci L, Zentilin L, Secco I, et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. 2019;569(7756):418–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lyu L, Zhao Y, Lu H, Liu Z, Guo J, Lu D, et al. Integrated interaction network of microRNA target genes in keloid scarring. Mol Diagn Ther. 2019;23(1):53–63.

    Article  CAS  PubMed  Google Scholar 

  23. Zhong L, Bian L, Lyu J, Jin H, Liu Z, Lyu L, et al. Identification and integrated analysis of microRNA expression profiles in keloid. J Cosmet Dermatol. 2018;17(5):917–24.

    Article  PubMed  Google Scholar 

  24. Ghafouri-Fard S, Abak A, Talebi SF, Shoorei H, Branicki W, Taheri M, et al. Role of miRNA and lncRNAs in organ fibrosis and aging. Biomed Pharmacother. 2021;143: 112132.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao H, Feng YL, Liu T, Wang JJ, Yu J. MicroRNAs in organ fibrosis: From molecular mechanisms to potential therapeutic targets. Pathol Res Pract. 2021;225: 153588.

    Article  CAS  PubMed  Google Scholar 

  26. Henry TW, Mendoza FA, Jimenez SA. Role of microRNA in the pathogenesis of systemic sclerosis tissue fibrosis and vasculopathy. Autoimmun Rev. 2019;18(11): 102396.

    Article  CAS  PubMed  Google Scholar 

  27. Li Y, Zhang J, Lei Y, Lyu L, Zuo R, Chen T. MicroRNA-21 in skin fibrosis: potential for diagnosis and treatment. Mol Diagn Ther. 2017;21(6):633–42.

    Article  CAS  PubMed  Google Scholar 

  28. Suzuki HI. MicroRNA control of TGF-beta signaling. Int J Mol Sci. 2018;19(7):1901.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jakob P, Landmesser U. Current status of cell-based therapy for heart failure. Curr Heart Fail Rep. 2013;10(2):165–76.

    Article  CAS  PubMed  Google Scholar 

  30. Kamps JA, Krenning G. Micromanaging cardiac regeneration: targeted delivery of microRNAs for cardiac repair and regeneration. World J Cardiol. 2016;8(2):163–79.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gurbuz N, Ozpolat B. MicroRNA-based targeted therapeutics in pancreatic cancer. Anticancer Res. 2019;39(2):529–32.

    Article  CAS  PubMed  Google Scholar 

  32. Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Luscher TF. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J. 2020;41(40):3884–99.

    Article  CAS  PubMed  Google Scholar 

  33. Miniarikova J, Evers MM, Konstantinova P. Translation of microRNA-based Huntingtin-lowering therapies from preclinical studies to the clinic. Mol Ther. 2018;26(4):947–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shatsberg Z, Zhang X, Ofek P, Malhotra S, Krivitsky A, Scomparin A, et al. Functionalized nanogels carrying an anticancer microRNA for glioblastoma therapy. J Control Release. 2016;10(239):159–68.

    Article  Google Scholar 

  35. Ruman U, Fakurazi S, Masarudin MJ, Hussein MZ. Nanocarrier-based therapeutics and theranostics drug delivery systems for next generation of liver cancer nanodrug modalities. Int J Nanomed. 2020;15:1437–56.

    Article  CAS  Google Scholar 

  36. Ma G, Lin W, Wang Z, Zhang J, Qian H, Xu L, et al. Development of polypeptide-based zwitterionic amphiphilic micelles for nanodrug delivery. J Mater Chem B. 2016;4(31):5256–64.

    Article  CAS  PubMed  Google Scholar 

  37. Wang Q, Jiang N, Fu B, Huang F, Liu J. Self-assembling peptide-based nanodrug delivery systems. Biomater Sci. 2019;7(12):4888–911.

    Article  CAS  PubMed  Google Scholar 

  38. Ghobadi AF, Jayaraman A. Effect of backbone chemistry on hybridization thermodynamics of oligonucleic acids: a coarse-grained molecular dynamics simulation study. Soft Matter. 2016;12(8):2276–87.

    Article  CAS  PubMed  Google Scholar 

  39. Jing Z, Qi R, Thibonnier M, Ren P. Molecular dynamics study of the hybridization between RNA and modified oligonucleotides. J Chem Theory Comput. 2019;15(11):6422–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Manicardi A, Gambari R, de Cola L, Corradini R. Preparation of anti-miR PNAs for drug development and nanomedicine. Methods Mol Biol. 2018;1811:49–63.

    Article  CAS  PubMed  Google Scholar 

  41. Kauppinen S, Vester B, Wengel J. Locked nucleic acid: high-affinity targeting of complementary RNA for RNomics. Handb Exp Pharmacol. 2006;173(173):405–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gallant-Behm CL, Piper J, Dickinson BA, Dalby CM, Pestano LA, Jackson AL. A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds. Wound Repair Regen. 2018;26(4):311–23.

    Article  PubMed  Google Scholar 

  43. Sanghvi YS, Schulte M. Therapeutic oligonucleotides: the state-of-the-art in purification technologies. Curr Opin Drug Discov Devel. 2004;7(6):765–76.

    CAS  PubMed  Google Scholar 

  44. Smith CIE, Zain R. Therapeutic oligonucleotides: state of the art. Annu Rev Pharmacol Toxicol. 2019;6(59):605–30.

    Article  Google Scholar 

  45. Fernandez Fernandez E, Santos-Carballal B, de Santi C, Ramsey JM, MacLoughlin R, Cryan SA, et al. Biopolymer-based nanoparticles for cystic fibrosis lung gene therapy studies. Materials (Basel). 2018;11(1):122.

    Article  PubMed  PubMed Central  Google Scholar 

  46. De Santi C, Nally FK, Afzal R, Duffy CP, Fitzsimons S, Annett SL, et al. Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype. Mol Ther Nucleic Acids. 2022;13(29):643–55.

    Article  Google Scholar 

  47. Kumar V, Kumar V, Luo J, Mahato RI. Therapeutic potential of OMe-PS-miR-29b1 for treating liver fibrosis. Mol Ther. 2018;26(12):2798–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kumar V, Mondal G, Dutta R, Mahato RI. Co-delivery of small molecule Hedgehog inhibitor and miRNA for treating liver fibrosis. Biomaterials. 2016;76:144–56.

    Article  CAS  PubMed  Google Scholar 

  49. Momen-Heravi F, Catalano D, Talis A, Szabo G, Bala S. Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice. Mol Ther Nucleic Acids. 2021;3(25):155–67.

    Article  Google Scholar 

  50. Ghosh N, Fenton S, van Hout I, Jones GT, Coffey S, Williams MJA, et al. Therapeutic knockdown of miR-320 improves deteriorated cardiac function in a pre-clinical model of non-ischemic diabetic heart disease. Mol Ther Nucleic Acids. 2022;13(29):330–42.

    Article  Google Scholar 

  51. Nonaka CKV, Sampaio GL, Silva KN, Khouri R, Macedo CT, Chagas Translational Research Consortium, et al. Therapeutic miR-21 silencing reduces cardiac fibrosis and modulates inflammatory response in chronic Chagas disease. Int J Mol Sci. 2021;22(7):3307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang XL, Zhang G, Bai ZH. miR-34a attenuates myocardial fibrosis in diabetic cardiomyopathy mice via targeting Pin-1. Cell Biol Int. 2021;45(3):642–53.

    Article  CAS  PubMed  Google Scholar 

  53. Hinkel R, Ramanujam D, Kaczmarek V, Howe A, Klett K, Beck C, et al. AntimiR-21 prevents myocardial dysfunction in a pig model of ischemia/reperfusion injury. J Am Coll Cardiol. 2020;75(15):1788–800.

    Article  CAS  PubMed  Google Scholar 

  54. Hao X, Luan J, Jiao C, Ma C, Feng Z, Zhu L, et al. LNA-anti-miR-150 alleviates renal interstitial fibrosis by reducing pro-inflammatory M1/M2 macrophage polarization. Front Immunol. 2022;13: 913007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Luan J, Fu J, Wang D, Jiao C, Cui X, Chen C, et al. miR-150-Based RNA interference attenuates tubulointerstitial fibrosis through the SOCS1/JAK/STAT pathway in vivo and in vitro. Mol Ther Nucleic Acids. 2020;4(22):871–84.

    Article  Google Scholar 

  56. Fluitt MB, Shivapurkar N, Kumari M, Singh S, Li L, Tiwari S, et al. Systemic inhibition of miR-451 increases fibrotic signaling and diminishes autophagic response to exacerbate renal damage in Tallyho/Jng mice. Am J Physiol Renal Physiol. 2020;319(3):F476–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sonneville F, Ruffin M, Coraux C, Rousselet N, Le Rouzic P, Blouquit-Laye S, et al. MicroRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology. Nat Commun. 2017;8(1):710.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Fabbri E, Tamanini A, Jakova T, Gasparello J, Manicardi A, Corradini R, et al. Treatment of human airway epithelial Calu-3 cells with a peptide-nucleic acid (PNA) targeting the microRNA miR-101-3p is associated with increased expression of the cystic fibrosis transmembrane conductance regulator () gene. Eur J Med Chem. 2021;1(209): 112876.

    Article  Google Scholar 

  59. Sultan S, Rozzi A, Gasparello J, Manicardi A, Corradini R, Papi C, et al. A peptide nucleic acid (PNA) masking the miR-145-5p binding site of the 3′UTR of the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA enhances CFTR expression in Calu-3 cells. Molecules. 2020;25(7):1677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fabbri E, Tamanini A, Jakova T, Gasparello J, Manicardi A, Corradini R, et al. A peptide nucleic acid against microRNA miR-145-5p enhances the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in Calu-3 cells. Molecules. 2017;23(1):71.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Fernandez Fernandez E, De Santi C, De Rose V, Greene CM. CFTR dysfunction in cystic fibrosis and chronic obstructive pulmonary disease. Expert Rev Respir Med. 2018;12(6):483–92.

    Article  CAS  PubMed  Google Scholar 

  62. McKiernan PJ, Greene CM. MicroRNA dysregulation in cystic fibrosis. Mediators Inflamm. 2015;2015: 529642.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ramachandran S, Karp PH, Osterhaus SR, Jiang P, Wohlford-Lenane C, Lennox KA, et al. Post-transcriptional regulation of cystic fibrosis transmembrane conductance regulator expression and function by microRNAs. Am J Respir Cell Mol Biol. 2013;49(4):544–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zarrilli F, Amato F, Morgillo CM, Pinto B, Santarpia G, Borbone N, et al. Peptide nucleic acids as miRNA target protectors for the treatment of cystic fibrosis. Molecules. 2017;22(7):1144.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Amato F, Tomaiuolo R, Nici F, Borbone N, Elce A, Catalanotti B, et al. Exploitation of a very small peptide nucleic acid as a new inhibitor of miR-509-3p involved in the regulation of cystic fibrosis disease-gene expression. Biomed Res Int. 2014;2014: 610718.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Megiorni F, Cialfi S, Cimino G, De Biase RV, Dominici C, Quattrucci S, et al. Elevated levels of miR-145 correlate with SMAD3 down-regulation in cystic fibrosis patients. J Cyst Fibros. 2013;12(6):797–802.

    Article  CAS  PubMed  Google Scholar 

  67. Papi C, Gasparello J, Zurlo M, Manicardi A, Corradini R, Cabrini G, et al. Combined treatment of bronchial epithelial Calu-3 cells with peptide nucleic acids targeting miR-145-5p and miR-101-3p: synergistic enhancement of the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Int J Mol Sci. 2022;23(16):9348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ahangari F, Price NL, Malik S, Chioccioli M, Barnthaler T, Adams TS, et al. microRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis. JCI Insight. 2023;8(4): e158100.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Price NL, Miguel V, Ding W, Singh AK, Malik S, Rotllan N, et al. Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis. JCI Insight. 2019;4(22): e131102.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Deng Z, He Y, Yang X, Shi H, Shi A, Lu L, et al. MicroRNA-29: a crucial player in fibrotic disease. Mol Diagn Ther. 2017;21(3):285–94.

    Article  CAS  PubMed  Google Scholar 

  71. Montgomery RL, Yu G, Latimer PA, Stack C, Robinson K, Dalby CM, et al. MicroRNA mimicry blocks pulmonary fibrosis. EMBO Mol Med. 2014;6(10):1347–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gallant-Behm CL, Piper J, Lynch JM, Seto AG, Hong SJ, Mustoe TA, et al. A microRNA-29 mimic (Remlarsen) represses extracellular matrix expression and fibroplasia in the skin. J Invest Dermatol. 2019;139(5):1073–81.

    Article  CAS  PubMed  Google Scholar 

  73. Beck C, Ramanujam D, Vaccarello P, Widenmeyer F, Feuerherd M, Cheng CC, et al. Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage. Nature Commun. 2023;14(1):4564.

    Article  CAS  Google Scholar 

  74. Ma C, Gerhard E, Lu D, Yang J. Citrate chemistry and biology for biomaterials design. Biomaterials. 2018;178:383–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Huang Y, Lu X, Qu Y, Yang Y, Wu S. MicroRNA sequencing and molecular mechanisms analysis of the effects of gold nanoparticles on human dermal fibroblasts. Biomaterials. 2015;37:13–24.

    Article  PubMed  Google Scholar 

  76. Chan MY, Vikesland PJ. Porous media-induced aggregation of protein-stabilized gold nanoparticles. Environ Sci Technol. 2014;48(3):1532–40.

    Article  CAS  PubMed  Google Scholar 

  77. Mohammadniaei M, Koyappayil A, Sun Y, Min J, Lee MH. Gold nanoparticle/MXene for multiple and sensitive detection of oncomiRs based on synergetic signal amplification. Biosens Bioelectron. 2020;1(159): 112208.

    Article  Google Scholar 

  78. Robinson PM, Chuang TD, Sriram S, Pi L, Luo XP, Petersen BE, et al. MicroRNA signature in wound healing following excimer laser ablation: role of miR-133b on TGFbeta1, CTGF, SMA, and COL1A1 expression levels in rabbit corneal fibroblasts. Invest Ophthalmol Vis Sci. 2013;54(10):6944–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhao X, Song W, Chen Y, Liu S, Ren L. Collagen-based materials combined with microRNA for repairing cornea wounds and inhibiting scar formation. Biomater Sci. 2018;7(1):51–62.

    Article  PubMed  Google Scholar 

  80. Jia C, Chen H, Wei M, Chen X, Zhang Y, Cao L, et al. Gold nanoparticle-based miR155 antagonist macrophage delivery restores the cardiac function in ovariectomized diabetic mouse model. Int J Nanomedicine. 2017;12:4963–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Paoletti A, Rohmer J, Ly B, Pascaud J, Riviere E, Seror R, et al. Monocyte/macrophage abnormalities specific to rheumatoid arthritis are linked to miR-155 and are differentially modulated by different TNF inhibitors. J Immunol. 2019;203(7):1766–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang Q, Song Y, Chen J, Li Q, Gao J, Tan H, et al. Direct in vivo reprogramming with non-viral sequential targeting nanoparticles promotes cardiac regeneration. Biomaterials. 2021;276: 121028.

    Article  CAS  PubMed  Google Scholar 

  83. Bharadwaz A, Jayasuriya AC. Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration. Mater Sci Eng C Mater Biol Appl. 2020;110: 110698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang J, Zhang L, Wang X, Fu S, Yan G. Acid-labile poly(amino alcohol ortho ester) based on low molecular weight polyethyleneimine for gene delivery. J Biomater Appl. 2017;32(3):349–61.

    Article  CAS  PubMed  Google Scholar 

  85. Wang X, Niu D, Hu C, Li P. Polyethyleneimine-based nanocarriers for gene delivery. Curr Pharm Des. 2015;21(42):6140–56.

    Article  CAS  PubMed  Google Scholar 

  86. Morishita Y, Imai T, Yoshizawa H, Watanabe M, Ishibashi K, Muto S, et al. Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo. Int J Nanomedicine. 2015;10:3475–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. McKiernan PJ, Cunningham O, Greene CM, Cryan SA. Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using nanotechnology. Int J Nanomedine. 2013;8:3907–15.

    Google Scholar 

  88. Muniyandi P, Palaninathan V, Mizuki T, Mohamed MS, Hanajiri T, Maekawa T. Scaffold mediated delivery of dual miRNAs to transdifferentiate cardiac fibroblasts. Mater Sci Eng C Mater Biol Appl. 2021;128: 112323.

    Article  CAS  PubMed  Google Scholar 

  89. Li Q, Li L, Yu M, Zheng M, Li Y, Yang J, et al. Elastomeric polyurethane porous film functionalized with gastrodin for peripheral nerve regeneration. J Biomed Mater Res A. 2020;108(8):1713–25.

    Article  CAS  PubMed  Google Scholar 

  90. Gong JH, Wang Y, Xing L, Cui PF, Qiao JB, He YJ, et al. Biocompatible fluorinated poly(beta-amino ester)s for safe and efficient gene therapy. Int J Pharm. 2018;535(1–2):180–93.

    Article  CAS  PubMed  Google Scholar 

  91. Yu Q, Xiong X, Zhao L, Xu T, Wang Q. Antifibrotic effects of specific siRNA targeting connective tissue growth factor delivered by polyethyleneimine-functionalized magnetic iron oxide nanoparticles on LX-2 cells. Mol Med Rep. 2020;21(1):181–90.

    CAS  PubMed  Google Scholar 

  92. De Santi C, Fernandez Fernandez E, Gaul R, Vencken S, Glasgow A, Oglesby IK, et al. Precise targeting of miRNA sites restores CFTR activity in CF bronchial epithelial cells. Mol Ther. 2020;28(4):1190–9.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Vencken S, Foged C, Ramsey JM, Sweeney L, Cryan SA, MacLoughlin RJ, et al. Nebulised lipid-polymer hybrid nanoparticles for the delivery of a therapeutic anti-inflammatory microRNA to bronchial epithelial cells. ERJ Open Res. 2019;5(2):00161–2018.

    Article  PubMed  PubMed Central  Google Scholar 

  94. McKiernan PJ, Lynch P, Ramsey JM, Cryan SA, Greene CM. Knockdown of gene expression in macrophages by microRNA mimic-containing poly(lactic-co-glycolic acid) microparticles. Medicines (Basel). 2018;5(4):133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Geng X, Zhang M, Lai X, Tan L, Liu J, Yu M, et al. Small-sized cationic miRi-PCNPs selectively target the kidneys for high-efficiency antifibrosis treatment. Adv Healthc Mater. 2018;7(21): e1800558.

    Article  PubMed  Google Scholar 

  96. Patel B, Gupta V, Ahsan F. PEG-PLGA based large porous particles for pulmonary delivery of a highly soluble drug, low molecular weight heparin. J Control Release. 2012;162(2):310–20.

    Article  CAS  PubMed  Google Scholar 

  97. Meenach SA, Kim YJ, Kauffman KJ, Kanthamneni N, Bachelder EM, Ainslie KM. Synthesis, optimization, and characterization of camptothecin-loaded acetalated dextran porous microparticles for pulmonary delivery. Mol Pharm. 2012;9(2):290–8.

    Article  CAS  PubMed  Google Scholar 

  98. Wu D, Wang C, Yang J, Wang H, Han H, Zhang A, et al. Improving the intracellular drug concentration in lung cancer treatment through the codelivery of doxorubicin and miR-519c mediated by porous PLGA microparticle. Mol Pharm. 2016;13(11):3925–33.

    Article  CAS  PubMed  Google Scholar 

  99. Roy H, Rahaman SA, Kumar TV, Nandi S. Current development on chitosan-based antimicrobial drug formulations for the wound healing. Curr Drug Discov Technol. 2020;17(4):534–41.

    Article  CAS  PubMed  Google Scholar 

  100. Chen Q, Lu H, Yang H. Chitosan inhibits fibroblasts growth in Achilles tendon via TGF-β1/Smad3 pathway by miR-29b. Int J Clin Exp Pathol. 2014;7(12):8462–70.

    PubMed  PubMed Central  Google Scholar 

  101. Wang Z, Wu G, Yang Z, Li X, Feng Z, Zhao Y. Chitosan/hyaluronic acid/microRNA-21 nanoparticle-coated smooth titanium surfaces promote the functionality of human gingival fibroblasts. Int J Nanomed. 2022;17:3793–807.

    Article  CAS  Google Scholar 

  102. Hwang DW, Kim HY, Li F, Park JY, Kim D, Park JH, et al. In vivo visualization of endogenous miR-21 using hyaluronic acid-coated graphene oxide for targeted cancer therapy. Biomaterials. 2017;121:144–54.

    Article  CAS  PubMed  Google Scholar 

  103. Wang Z, Zang A, Wei Y, An L, Hong D, Shi Y, et al. Hyaluronic acid capped, irinotecan and gene co-loaded lipid-polymer hybrid nanocarrier-based combination therapy platform for colorectal cancer. Drug Des Devel Ther. 2020;14:1095–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bejerano T, Etzion S, Elyagon S, Etzion Y, Cohen S. Nanoparticle delivery of miRNA-21 mimic to cardiac macrophages improves myocardial remodeling after myocardial infarction. Nano Lett. 2018;18(9):5885–91.

    Article  CAS  PubMed  Google Scholar 

  105. Sun X, Song W, Teng L, Huang Y, Liu J, Peng Y, et al. MiRNA 24–3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing. Bioactive Mater. 2023;25:640–56.

    Article  CAS  Google Scholar 

  106. Wahane A, Waghmode A, Kapphahn A, Dhuri K, Gupta A, Bahal R. Role of lipid-based and polymer-based non-viral vectors in nucleic acid delivery for next-generation gene therapy. Molecules. 2020;25(12):2866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Scheideler M, Vidakovic I, Prassl R. Lipid nanocarriers for microRNA delivery. Chem Phys Lipids. 2020;226: 104837.

    Article  CAS  PubMed  Google Scholar 

  108. Sosnowska K, Szymanska E, Winnicka K. Nanoemulsion with clotrimazole: design and optimalization of mean droplet size using microfluidization technique. Acta Pol Pharm. 2017;74(2):519–26.

    CAS  PubMed  Google Scholar 

  109. Halasz T, Horvath G, Par G, Werling K, Kiss A, Schaff Z, et al. miR-122 negatively correlates with liver fibrosis as detected by histology and FibroScan. World J Gastroenterol. 2015;21(25):7814–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yan L, Su Y, Hsia I, Xu Y, Vincent-Chong VK, Mojica W, et al. Delivery of anti-microRNA-21 by lung-targeted liposomes for pulmonary fibrosis treatment. Mol Ther Nucleic Acids. 2023;13(32):36–47.

    Article  CAS  Google Scholar 

  111. Wang X, Yu B, Ren W, Mo X, Zhou C, He H, et al. Enhanced hepatic delivery of siRNA and microRNA using oleic acid based lipid nanoparticle formulations. J Control Release. 2013;172(3):690–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Moon S, Shin DW, Kim S, Lee YS, Mankhong S, Yang SW, et al. Enrichment of exosome-like extracellular vesicles from plasma suitable for clinical vesicular miRNA biomarker research. J Clin Med. 2019;8(11):1995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ohno S, Kuroda M. Exosome-mediated targeted delivery of miRNAs. Methods Mol Biol. 2016;1448:261–70.

    Article  CAS  PubMed  Google Scholar 

  114. Mobergslien A, Sioud M. Exosome-derived miRNAs and cellular miRNAs activate innate immunity. J Innate Immun. 2014;6(1):105–10.

    Article  CAS  PubMed  Google Scholar 

  115. Qin XJ, Zhang JX, Wang RL. Exosomes as mediators and biomarkers in fibrosis. Biomark Med. 2020;14(8):697–712.

    Article  CAS  PubMed  Google Scholar 

  116. Sun L, Zhu M, Feng W, Lin Y, Yin J, Jin J, et al. Exosomal miRNA Let-7 from menstrual blood-derived endometrial stem cells alleviates pulmonary fibrosis through regulating mitochondrial DNA damage. Oxid Med Cell Longev. 2019;2019:4506303.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Bier A, Berenstein P, Kronfeld N, Morgoulis D, Ziv-Av A, Goldstein H, et al. Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy. Biomaterials. 2018;174:67–78.

    Article  CAS  PubMed  Google Scholar 

  118. Yang L, Wang T, Zhang X, Zhang H, Yan N, Zhang G, et al. Exosomes derived from human placental mesenchymal stem cells ameliorate myocardial infarction via anti-inflammation and restoring gut dysbiosis. BMC Cardiovasc Disord. 2022;22(1):61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Venkat P, Cui C, Chen Z, Chopp M, Zacharek A, Landschoot-Ward J, et al. CD133+exosome treatment improves cardiac function after stroke in type 2 diabetic mice. Transl Stroke Res. 2021;12(1):112–24.

    Article  CAS  PubMed  Google Scholar 

  120. Luo Q, Guo D, Liu G, Chen G, Hang M, Jin M. Exosomes from MiR-126-overexpressing Adscs are therapeutic in relieving acute myocardial ischaemic injury. Cell Physiol Biochem. 2017;44(6):2105–16.

    Article  CAS  PubMed  Google Scholar 

  121. Wang X, Zhu Y, Wu C, Liu W, He Y, Yang Q. Adipose-derived mesenchymal stem cells-derived exosomes carry microRNA-671 to alleviate myocardial infarction through inactivating the TGFBR2/Smad2 axis. Inflammation. 2021;44(5):1815–30.

    Article  CAS  PubMed  Google Scholar 

  122. Pan J, Alimujiang M, Chen Q, Shi H, Luo X. Exosomes derived from miR-146a-modified adipose-derived stem cells attenuate acute myocardial infarction-induced myocardial damage via downregulation of early growth response factor 1. J Cell Biochem. 2019;120(3):4433–43.

    Article  CAS  PubMed  Google Scholar 

  123. Zhao Y, Du L, Sun J, Wang X, Cong Z, Chen S, et al. Exosomal miR-218 derived from mesenchymal stem cells inhibits endothelial-to-mesenchymal transition by epigenetically modulating of BMP2 in pulmonary fibrosis. Cell Biol Toxicol. 2023. https://doi.org/10.1007/s10565-023-09810-z.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Wu D, Liu X, Jin Z. Adipose-derived mesenchymal stem cells-sourced exosomal microRNA-7846-3p suppresses proliferation and pro-angiogenic role of keloid fibroblasts by suppressing neuropilin 2. J Cosmet Dermatol. 2023;22(8):2333–42.

    Article  PubMed  Google Scholar 

  125. Xu S, Cheuk YC, Jia Y, Chen T, Chen J, Luo Y, et al. Bone marrow mesenchymal stem cell-derived exosomal miR-21a-5p alleviates renal fibrosis by attenuating glycolysis by targeting PFKM. Cell Death Dis. 2022;13(10):876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Xie L, Long X, Mo M, Jiang J, Zhang Q, Long M, et al. Bone marrow mesenchymal stem cell-derived exosomes alleviate skin fibrosis in systemic sclerosis by inhibiting the IL-33/ST2 axis via the delivery of microRNA-214. Mol Immunol. 2023;157:146–57.

    Article  CAS  PubMed  Google Scholar 

  127. Liu Q, Bi Y, Song S, Zhu K, Qiao X, Wang H, et al. Exosomal miR-17-5p from human embryonic stem cells prevents pulmonary fibrosis by targeting thrombospondin-2. Stem Cell Res Ther. 2023;14(1):234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lang Z, Li Y, Lin L, Li X, Tao Q, Hu Y, et al. Hepatocyte-derived exosomal miR-146a-5p inhibits hepatic stellate cell EMT process: a crosstalk between hepatocytes and hepatic stellate cells. Cell Death Discov. 2023;9(1):304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li F, Yan T, Wang S, Wen X. Exosome-associated miRNA-99a-5p targeting BMPR2 promotes hepatocyte apoptosis during the process of hepatic fibrosis. Clin Exp Med. 2023. https://doi.org/10.1007/s10238-023-01122-0.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Ji JL, Shi HM, Li ZL, Jin R, Qu GT, Zheng H, et al. Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates the renal tubulointerstitial fibrosis in mouse diabetic nephropathy. Acta Pharmacol Sin. 2023. https://doi.org/10.1038/s41401-023-01140-4.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Chen YH, Xu YC, Lin TT, Chen H, Dong RN, Cai FP, et al. Exosomal MiR-381 from M2-polarized macrophages attenuates urethral fibroblasts activation through YAP/GLS1-regulated glutaminolysis. Inflamm Res. 2023;72(7):1359–73.

    Article  CAS  PubMed  Google Scholar 

  132. Wang J, Tao Y, Zhao F, Liu T, Shen X, Zhou L. Expression of urinary exosomal miRNA-615-3p and miRNA-3147 in diabetic kidney disease and their association with inflammation and fibrosis. Ren Fail. 2023;45(1):2121929.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Ding M, Pei Y, Zhang C, Qi Y, Xia J, Hao C, et al. Exosomal miR-125a-5p regulates T lymphocyte subsets to promote silica-induced pulmonary fibrosis by targeting TRAF6. Ecotoxicol Environ Saf. 2023;1(249): 114401.

    Article  Google Scholar 

  134. Zhang KL, Wang YJ, Sun J, Zhou J, Xing C, Huang G, et al. Artificial chimeric exosomes for anti-phagocytosis and targeted cancer therapy. Chem Sci. 2019;10(5):1555–61.

    Article  CAS  PubMed  Google Scholar 

  135. Zhang Z, Dombroski JA, King MR. Engineering of exosomes to target cancer metastasis. Cell Mol Bioeng. 2020;13(1):1–16.

    Article  PubMed  Google Scholar 

  136. Zhu L, Bao L, Zhang X, Xia X, Sun H. Inhibition of porcine reproductive and respiratory syndrome virus replication with exosome-transferred artificial microRNA targeting the 3’ untranslated region. J Virol Methods. 2015;223:61–8.

    Article  CAS  PubMed  Google Scholar 

  137. Meng S, Wei Q, Chen S, Liu X, Cui S, Huang Q, et al. MiR-141-3p-functionalized exosomes loaded in dissolvable microneedle arrays for hypertrophic scar treatment. Small. 2023;18: e2305374.

    Article  Google Scholar 

  138. Yuan J, Yang H, Liu C, Shao L, Zhang H, Lu K, et al. Microneedle patch loaded with exosomes containing microRNA-29b prevents cardiac fibrosis after myocardial infarction. Adv Healthc Mater. 2023;12(13): e2202959.

    Article  PubMed  Google Scholar 

  139. Wei J, Han X, Zhang C, Liao W, Qin X, Li L, et al. Intracellular delivery of microRNA therapeutics based on nanocarriers: current status and future perspective. Mater Rep. 2019;33(1):16–26.

    Google Scholar 

  140. Bai Z, Wei J, Yu C, Han X, Qin X, Zhang C, et al. Non-viral nanocarriers for intracellular delivery of microRNA therapeutics. J Mater Chem B. 2019;7(8):1209–25.

    Article  CAS  PubMed  Google Scholar 

  141. Fernandez-Pineiro I, Badiola I, Sanchez A. Nanocarriers for microRNA delivery in cancer medicine. Biotechnol Adv. 2017;35(3):350–60.

    Article  CAS  PubMed  Google Scholar 

  142. Meng Z, Zhou D, Gao Y, Zeng M, Wang W. miRNA delivery for skin wound healing. Adv Drug Deliv Rev. 2018;129:308–18.

    Article  CAS  PubMed  Google Scholar 

  143. Hashemi A, Gorji-Bahri G. MicroRNA: promising roles in cancer therapy. Curr Pharm Biotechnol. 2020;21(12):1186–203.

    Article  CAS  PubMed  Google Scholar 

  144. Zhang D, Lee H, Jin Y. Delivery of functional small RNAs via extracellular vesicles in vitro and in vivo. Methods Mol Biol. 2020;2115:107–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Yanfang Guo, Hanying Wang and Rumin Lyu are contributed equally to this work and should be considered joint first authors.

Authors and Affiliations

  1. Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, NHC Key Laboratory of Drug Addiction Medicine, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, 650500, Yunnan, China

    Yanfang Guo, Hanying Wang, Rumin Lyu, Juan Wang, Ting Wang, Jingpei Shi & Lechun Lyu

  2. Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Kunming Medical University, Kunming, 650106, Yunnan, China

    Jingpei Shi

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  1. Yanfang Guo
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Correspondence to Jingpei Shi or Lechun Lyu.

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This article was supported by grants from the National Natural Science Foundation of China (grant nos. 81960354, 82360447), the Joint Fund for Basic Research of Yunnan Provincial Department of Science and Technology and Kunming Medical University (202101AY070001-012, 202001AY070001-014), Kunming Science and Technology Plan Project (2019-1-N-25318000003496) and Bai Xiaochun expert workstation (YSZJGZZ-2020040).

Conflicts of Interest

Yanfang Guo, Hanying Wang, Rumin Lyu, Juan Wang, Ting Wang, Jingpei Shi and Lechun Lyu have no conflicts of interest that are directly relevant to the content of this article.

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Authors’ Contributions

LL and JS contributed to the conception. YG, HW, RL, JW, and TW performed the experiments. LL and JS wrote the original draft. All the authors have reviewed the final manuscript.

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Guo, Y., Wang, H., Lyu, R. et al. Nanocarrier-Mediated Delivery of MicroRNAs for Fibrotic Diseases. Mol Diagn Ther 28, 53–67 (2024). https://doi.org/10.1007/s40291-023-00681-y

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