Lipid nanoparticles silence tumor necrosis factor α to improve wound healing in diabetic mice

Diabetes mellitus is a mounting concern in the United States, as are the mortality and morbidity that result from its complications. Of particular concern, diabetes patients frequently suffer from impaired wound healing and resultant nonhealing diabetic foot ulcers. These ulcers overproduce tumor necrosis factor alpha (TNF alpha), which reduces wound bed cell migration and proliferation while encouraging apoptosis. Herein, we describe the use of siRNA-loaded lipid nanoparticles (LNPs) as a potential wound treatment to combat an overzealous immune response and facilitate wound closure. LNPs were formulated with an ionizable, degradable lipidoid and siRNA specific for TNF alpha. Topical application of nanoparticles reduced TNF alpha mRNA expression in the wound by 40-55% in diabetic and nondiabetic mice. In diabetic mice, this TNF alpha knockdown accelerated wound healing compared to untreated controls. Together, these results serve as proof-of-concept that RNA interference therapy using LNPs can reduce the severity and duration of chronic diabetic wounds.