Nonhealing wounds have been the subject of decades of basic and clinical research. Despite new knowledge about the biology of impaired wound healing, little progress has been made in treating chronic wounds, leaving patients with few therapeutic options. Diabetic ulcers are a particularly common form of nonhealing wound.Recently, investigation of therapeutic nucleic acids (TNAs), including plasmid DNA, small interfering RNA, microRNA mimics, anti-microRNA oligonucleotides, messenger RNA, and antisense oligonucleotides, has created a new treatment strategy for chronic wounds. TNAs can modulate the wound toward a prohealing environment by targeting gene pathways associated with inflammation, proteases, cell motility, angiogenesis, epithelialization, and oxidative stress. A variety of delivery systems have been investigated for TNAs, including dendrimers, lipid nanoparticles (NPs), polymeric micelles, polyplexes, metal NPs, and hydrogels. This review summarizes recent developments in TNA delivery for therapeutic targets associated with chronic wounds, with an emphasis on diabetic ulcers.Translational potential of TNAs remains a key challenge; we highlight some drug delivery approaches for TNAs that may hold promise. We also describe current commercial efforts to locally deliver nucleic acids to modulate the wound environment.Localized nucleic acid delivery holds promise for the treatment of nonhealing chronic wounds. Future efforts to improve targeting of these nucleic acid therapies in the wound with both spatial and temporal control through drug delivery systems will be crucial to successful clinical translation. Significance: Recent Advances: Critical Issues: Future Directions:
