Abstract
Though wound care has advanced, treating chronic wounds remains a challenge and there are many clinical issues that must be addressed. Gene therapy is a recent approach to treating chronic wounds that remains in its developmental stage. The limited reports available describe the therapeutic applications of various forms of nucleic acid delivery for treating chronic wounds, including DNA, mRNA, siRNA, miRNA and so on. Though these bioactive molecules represent great therapeutic potential, sustaining their bioactivity in the wound bed is a challenge. To overcome this hurdle, delivery systems are also being widely investigated. In this review, nucleic acid-based therapy and its delivery for treating chronic wounds is discussed in detail.
Graphical abstract
References
- 1. . Biochemistry of human skin – our brain on the outside. Chem. Soc. Rev. 35(1), 52–67 (2006).
- 2. . Anatomy, histology and immunohistochemistry of normal human skin. Eur. J. Dermatol. 12(4), 390–401 (2002).
- 3. . MicroRNAs in skin and wound healing. Methods Mol. Biol. 936, 343–356 (2013).
- 4. . Gene and Cell Therapy: Therapeutic Mechanisms and Strategies. (4th Edition). CRC Press (2015).
- 5. . MicroRNA as therapeutic targets for chronic wound healing. Mol. Ther. Nucleic Acids 8, 46–55 (2017).
- 6. . Wound repair and regeneration. Nature 453(7193), 314–321 (2008).
- 7. . Wound repair and regeneration. ESR 49(1), 35–43 (2012).
- 8. . Approaches to modulate the chronic wound environment using localized nucleic acid delivery. Adv. Wound Care (2020).
- 9. . Principles of Wound Healing. University of Adelaide Press, Adelaide, Australia (2011).
- 10. . Wound repair in the context of extracellular matrix. Curr. Opin. Cell Biol. 6(5), 717–725 (1994).
- 11. . Growth factors and wound healing: part II. Role in normal and chronic wound healing. Am. J. Surg. 166(1), 74–81 (1993).
- 12. . Growth factors and wound healing: biochemical properties of growth factors and their receptors. Am. J. Surg. 165(6), 728–737 (1993).
- 13. . Cytokines, growth factors, and plastic surgery. Plast. Reconstr. Surg. 108(3), 719–733 (2001).
- 14. . Macrophage-induced neutrophil apoptosis. J. Immunol. 165(1), 435–441 (2000).
- 15. . Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8(12), 958–969 (2008).
- 16. . Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast. Reconstr. Surg. 117(Suppl. 7), S35–S41 (2006).
- 17. . Hydrogel scaffolds for tissue engineering: progress and challenges. Glob. Cardiol. Sci. Pract. 2013(3), 38 (2013).
- 18. . Topical antimicrobial therapy for treating chronic wounds. Clin. Infect. Dis. 49(10), 1541–1549 (2009).
- 19. . A comparison of postprocedural wound care treatments: do antibiotic-based ointments improve outcomes? J. Am. Acad. Dermatol. 64(Suppl. 3), S23–S29 (2011).
- 20. . Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy. J. Foot Ankle Surg. 41(4), 233–237 (2002).
- 21. . Hyperbaric oxygen therapy and negative pressure as advanced wound management. Mol. Med. 116(3), 192–194 (2019).
- 22. The humanistic and economic burden of chronic wounds: a systematic review. Wound Repair Regen. 27(1), 114–125 (2019).
- 23. Gene expression profiling of cutaneous wound healing. J. Transl. Med. 5(1), 11 (2007).
- 24. . Approaches to modulate the chronic wound environment using localized nucleic acid delivery. Adv. Wound Care 10, 503–528 (2020).
- 25. siRNA knockdown of tissue inhibitor of metalloproteinase-1 in keloid fibroblasts leads to degradation of collagen type I. J. Invest. Dermatol. 134(3), 818–826 (2014).
- 26. . A collagen-based scaffold delivering exogenous microRNA-29B to modulate extracellular matrix remodeling. Mol. Ther. 22(4), 786–796 (2014).
- 27. . Liposomal IGF-1 gene transfer modulates pro- and anti-inflammatory cytokine mRNA expression in the burn wound. Gene Ther. 8(18), 1409–1415 (2001).
- 28. . Modulating inflammation in a cutaneous chronic wound model by IL-10 released from collagen–silica nanocomposites via gene delivery. Biomater. Sci. 6(2), 398–406 (2018).
- 29. . In vitro and in vivo epidermal growth factor gene therapy for diabetic ulcers with electrospun fibrous meshes. Acta Biomater. 9(7), 7371–7380 (2013).
- 30. . Serum response factor promotes re-epithelialization and muscular structure restoration during gastric ulcer healing. Gastroenterology 126(7), 1809–1818 (2004).
- 31. . Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in Type 1 diabetic mice. Circulation 110(16), 2484–2493 (2004).
- 32. A new technique of ex vivo gene delivery of VEGF to wounds using genetically modified skin particles promotes wound angiogenesis. J. Am. Coll. Surg. 212(3), 340–348 (2011).
- 33. Gene delivery of a mutant TGFβ3 reduces markers of scar tissue formation after cutaneous wounding. Mol. Ther. 18(12), 2104–2111 (2010).
- 34. The candidate tumor suppressor gene Ecrg4 as a wound terminating factor in cutaneous injury. Arch. Dermatol. Res. 305(2), 141–149 (2013).
- 35. . Design of gene-activated matrix for the repair of skin and cartilage. Polym. J. 46(8), 476–482 (2014).
- 36. . Developing a gene-activated matrix product for chronic wounds: a biotech's perspective. In: Advances in Wound Care: Volume 1 Mary Ann Liebert, Inc., NY, USA (2010).
- 37. . Biomedical application of plasmid DNA in gene therapy: a new challenge for chromatography. Biotechnol. Genet. Eng. Rev. 26, 83–116 (2010).
- 38. Transfection with aFGF cDNA improves wound healing. J. Invest. Dermatol. 108(3), 313–318 (1997).
- 39. Direct gene transfer into mouse muscle in vivo. Science 247(4949 Pt 1), 1465–1468 (1990).
- 40. . RNA therapies explained. Nature 574(7778), S2–S3 (2019).
- 41. Single-dose mRNA therapy via biomaterial-mediated sequestration of overexpressed proteins. Sci. Adv. 6(27), eaba2422 (2020).
- 42. . MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim. Biophys. Acta Mol. Cell Res. 1803(11), 1231–1243 (2010).
- 43. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat. Genet. 38(3), 356–362 (2006).
- 44. . microRNA in cutaneous wound healing. In: Current Perspectives in microRNAs (miRNA). Ying S-Y (Ed.). Springer, Dordrecht, The Netherlands (2008).
- 45. Molecular mechanisms and biological functions of siRNA. Int. J. Biomed. Sci. 13(2), 48–57 (2017).
- 46. Efficient gene expression in skin wound sites following local plasmid injection. J. Invest. Dermatol. 116(1), 131–135 (2001).
- 47. . Topical delivery of nucleic acids in the skin. STP Pharm. Sci. 11(1), 57 (2001).
- 48. . Viral and nonviral delivery systems for gene delivery. Adv. Biomed. Res. 1, 27 (2012).
- 49. . Gene delivery systems: recent progress in viral and non-viral therapy. Recent Advances in Novel Drug Delivery Carrier Systems. Sezer AD (Ed.). IntechOpen, London, UK (2012).
- 50. 152 retroviral gene therapy with the gene for PDGF-B promotes wound healing in diabetic mice. Wound Repair Regen. 13(2), A28–A48 (2005).
- 51. Strategies to enhance transductional efficiency of adenoviral-based gene transfer to primary human fibroblasts and keratinocytes as a platform in dermal wounds. Wound Repair Regen. 14(5), 608–617 (2006).
- 52. In vivo gene delivery of Ad-VEGF121 to full-thickness wounds in aged pigs results in high levels of VEGF expression but not in accelerated healing. Wound Repair Regen. 13(1), 51–60 (2005).
- 53. Engineering herpes simplex virus vectors for human gene therapy. Adv. Pharmacol. 40, 103–136 (1997).
- 54. . Lentiviral gene transfer of SDF-1alpha to wounds improves diabetic wound healing. J. Surg. Res. 143(1), 35–42 (2007).
- 55. . Lipid and polymeric carrier-mediated nucleic acid delivery. Expert Opin. Drug Deliv. 7(10), 1209–1226 (2010).
- 56. . Chitosan for gene delivery: methods for improvement and applications. Adv. Colloid Interface Sci. 268, 25–38 (2019).
- 57. . Polyethylenimine-based non-viral gene delivery systems. Eur. J. Pharm. Biopharm. 60(2), 247–266 (2005).
- 58. . Dendrimers for drug delivery. Molecules 23(4), 938 (2018). www.mdpi.com/1420-3049/23/4/938
- 59. . Bioconjugated Oligonucleotides: Recent Developments and Therapeutic Applications. Bioconjug. Chem. 30(2), 366–383 (2019).
- 60. Gene therapy vectors with enhanced transfection based on hydrogels modified with affinity peptides. Biomaterials 32(22), 5092–5099 (2011).
- 61. . Phosphatidylserine immobilization of lentivirus for localized gene transfer. Biomaterials 31(15), 4353–4359 (2010).
- 62. . Lentivirus delivery by adsorption to tissue engineering scaffolds. J. Biomed. Mater. Res. A 93(4), 1252–1259 (2010).
- 63. . Cytokine gene expression in epidermis with biological effects following injection of naked DNA. Nat. Genet. 10(2), 161–166 (1995).
- 64. In vivo gene transfer to skin and wound by microseeding. J. Surg. Res. 78(2), 85–91 (1998).
- 65. . Particle-mediated gene transfer of PDGF isoforms promotes wound repair. J. Invest. Dermatol. 112(3), 297–302 (1999).
- 66. Therapeutic success and efficacy of nonviral liposomal cDNA gene transfer to the skin in vivo is dose dependent. Gene Ther. 8(23), 1777–1784 (2001).
- 67. Matrix immobilization enhances the tissue repair activity of growth factor gene therapy vectors. Hum. Gene Ther. 12(7), 783–798 (2001).
- 68. . Augmentation of wound healing with translation initiation factor eIF4E mRNA. J. Surg. Res. 103(2), 175–182 (2002).
- 69. Improved diabetic wound healing through topical silencing of p53 is associated with augmented vasculogenic mediators. Wound Repair Regen. 18(6), 553–559 (2010).
- 70. Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing. Sci Rep. 8(1), 17509 (2018).
- 71. Regulation of impaired angiogenesis in diabetic dermal wound healing by microRNA-26a. J. Mol. Cell. Cardiol. 91, 151–159 (2016).
- 72. Single-dose mRNA therapy via biomaterial-mediated sequestration of overexpressed proteins. Sci. Adv. 6(27), eaba2422 (2020).
- 73. siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown. Proc. Natl Acad. Sci. USA 112(18), 5573–5578 (2015).
- 74. Local delivery of PHD2 siRNA from ROS-degradable scaffolds to promote diabetic wound healing. Adv. Healthc. Mater. 5(21), 2751–2757 (2016).
- 75. AntihypoxamiR functionalized gramicidin lipid nanoparticles rescue against ischemic memory improving cutaneous wound healing. Nanomedicine 12(7), 1827–1831 (2016).
- 76. . Over-expression of miR-223 induces M2 macrophage through glycolysis alteration and attenuates LPS-induced sepsis mouse model, the cell-based therapy in sepsis. PLOS ONE 15(7), e0236038 (2020).
- 77. Sustained delivery of MMP-9 siRNA via thermosensitive hydrogel accelerates diabetic wound healing. J. Nanobiotechnol. 19(1), 130 (2021).
- 78. Delivery of plasmid DNA expression vector for keratinocyte growth factor-1 using electroporation to improve cutaneous wound healing in a septic rat model. Wound Rep. Regen. 14(5), 618–624 (2006).
- 79. Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular endothelial growth factor DNA and a cationic dendrimer. J. Gene Med. 14(4), 272–278 (2012).
- 80. . The healing of full-thickness burns treated by using plasmid DNA encoding VEGF-165 activated collagen-chitosan dermal equivalents. Biomaterials 32(4), 1019–1031 (2011).
- 81. Antimicrobial peptide modification enhances the gene delivery and bactericidal efficiency of gold nanoparticles for accelerating diabetic wound healing. Biomater. Sci. 6(10), 2757–2772 (2018).
- 82. In situ formed anti-inflammatory hydrogel loading plasmid DNA encoding VEGF for burn wound healing. Acta Biomater. 100, 191–201 (2019).
- 83. Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression. Clin. Sci. (Lond) 114(12), 707–718 (2008).
- 84. . Intradermal injection of transforming growth factor-beta1 gene enhances wound healing in genetically diabetic mice. Pharm. Res. 20(3), 345–350 (2003).
- 85. . Current prospects for mRNA gene delivery. Eur. J. Pharm. Biopharm. 71(3), 484–489 (2009).
- 86. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nat. Commun. 10(1), 871 (2019).
- 87. Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J. 19(14), 2005–2007 (2005).
- 88. Granulocyte/macrophage colony-stimulating factor treatment of human chronic ulcers promotes angiogenesis associated with de novo vascular endothelial growth factor transcription in the ulcer bed. Br. J. Dermatol. 154(1), 34–41 (2006).
- 89. Anti-microRNA-378a enhances wound healing process by upregulating integrin beta-3 and vimentin. Mol. Ther. 22(10), 1839–1850 (2014).
- 90. MicroRNA-200b/c-3p regulate epithelial plasticity and inhibit cutaneous wound healing by modulating TGF-β-mediated RAC1 signaling. Cell Death Dis. 11(10), 1–17 (2020).
- 91. Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis. Oncotarget 8(46), 80651–80665 (2017).
- 92. Topical lyophilized targeted lipid nanoparticles in the restoration of skin barrier function following burn wound. Mol. Ther. 26(9), 2178–2188 (2018).
- 93. . Light-inducible antimiR-92a as a therapeutic strategy to promote skin repair in healing-impaired diabetic mice. Nat. Commun. 8(1), 15162 (2017).
- 94. MicroRNA-615-5p regulates angiogenesis and tissue repair by targeting AKT/eNOS (protein kinase B/endothelial nitric oxide synthase) signaling in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 39(7), 1458–1474 (2019).
- 95. MicroRNA miR-27b rescues bone marrow–derived angiogenic cell function and accelerates wound healing in type 2 diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 34(1), 99–109 (2014).
- 96. MicroRNA-149 contributes to scarless wound healing by attenuating inflammatory response. Mol. Med. Rep. 16(2), 2156–2162 (2017).
- 97. Local immunomodulation using an adhesive hydrogel loaded with miRNA-laden nanoparticles promotes wound healing. Small 15(36), 1902232 (2019).
- 98. MicroRNA-148b targets the TGF-β pathway to regulate angiogenesis and endothelial-to-mesenchymal transition during skin wound healing. Mol. Ther. 26(8), 1996–2007 (2018).
- 99. Development of microRNA-21 mimic nanocarriers for the treatment of cutaneous wounds. Theranostics 10(7), 3240–3253 (2020).
- 100. Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats. Int. J. Nurs. 9(1), 3377–3387 (2014).
- 101. A potential mechanism for diabetic wound healing: cutaneous environmental disorders. In: Wound Healing - New insights into Ancient Challenges [Internet]. Alexandrescu VA (Ed.). IntechOpen, London (2016).
- 102. . Lipid nanoparticles silence tumor necrosis factor α to improve wound healing in diabetic mice. Bioeng. Transl. Med. 4(1), 75–82 (2018).
- 103. . Silencing TNFα with lipidoid nanoparticles downregulates both TNFα and MCP-1 in an in vitro co-culture model of diabetic foot ulcers. Acta Biomater. 32, 120–128 (2016).
- 104. Fidgetin-like 2 siRNA enhances the wound healing capability of a surfactant polymer dressing. Adv. Wound Care 8(3), 91–100 (2019).
- 105. . RNAi for silencing drug resistance in microbes toward development of nanoantibiotics. J.Control. Release 189, 150–157 (2014).
- 106. . Transdermal siRNA-TGFβ1–337 patch for hypertrophic scar treatment. Matrix Biol. 32(5), 265–276 (2013).
- 107. Tissue Repair Company. Growth factor gene therapy for wound healing. clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT00065663
- 108. University of Pennsylvania. Phase I trial to evaluate the safety of platelet-derived growth factor B (PDGF-B) and a limb compression bandage in venous leg ulcers. clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT00000431
- 109. Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy. Ann. Clin. Transl. Neurol. 2(5), 465–478 (2015).
- 110. . VEGF gene transfer for critical limb ischemia. clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT00304837
- 111. AnGes USA, Inc. A phase II double-blind, randomized, placebo-controlled study to assess the safety and efficacy of AMG0001 to improve perfusion in critical limb ischemia in subjects who have peripheral ischemic ulcers. clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT00060892
- 112. Gene therapy for diabetic peripheral neuropathy: a randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor. Clin. Transl. Sci. 14(3), 1176–1184 (2021).
- 113. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nat. Med. 28(4), 780–788 (2022).