期刊
BIOMATERIALS
卷 132, 期 -, 页码 1-15出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.04.001
关键词
siRNA; Lipoproteoplex vehicle; Nrf2; Keap1; Diabetic wound; Gene therapy
资金
- American Diabetes Association [1-16-ACE-08]
- NYU Applied Research Support Fund
- National Science Foundation [DMR-1505214, IIP-144983]
- Division Of Materials Research
- Direct For Mathematical & Physical Scien [1505214] Funding Source: National Science Foundation
Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components. Published by Elsevier Ltd.
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