siRNA Loaded Lipidoid Nanoparticles for the Treatment of Diabetic Foot Ulcers and Chronic Inflammatory States

Himali Ranade

Research Poster Abstract

siRNA Loaded Lipidoid Nanoparticles for the Treatment of Diabetic Foot Ulcers and Chronic Inflammatory States

               

Diabetic foot ulcers are a serious condition that affects millions of diabetics worldwide, with many leading to lower leg amputation and an increased risk of death. These ulcers are characterized by vasculature dysfunction, infection, and most notably, chronic inflammation. Macrophages in the wound overproduce the inflammatory protein Tumor Necrosis Factor α (TNF-α), which then upregulates the production of Monocyte Chemoattractant Protein-1 (MCP-1) by fibroblasts and contributes to increased macrophage infiltration. Knocking down the overexpression of these two cytokines with RNA interference therapy is a possible solution to improve wound healing. In this work we explore the use of topically applied short interfering RNA loaded lipidoid nanoparticles to silence TNFα within the wound bed.  A topical approach is preferred over systemic or intravenous application as it offers direct and localized treatment, and reduces the incidence of side effects. We have shown that a 100 nM dose of siTNFα silences TNFα in macrophages by 65% with an EC₅₀ of 40 nM. Recent testing with juxtacrine and paracrine co-cultures of both cell types shows that both TNFα and MCP-1 can be silenced together. In these co-culture experiments, a single lipidoid nanoparticle of 100 nM siTNFα downregulated TNFα and MCP-1 by 64% and 32%, respectively, showing that one nanoparticle can knock down both proteins. By mimicking the environment and achieving successful silencing, it can be hypothesized that similar silencing patterns will occur in vivo. Future work will involve further recreating the wound environment by incorporating nucleases and fatty acids. The successful gene silencing and protein knockdown that has been achieved thus far is promising, and suggests that a siRNA loaded lipidoid nanoparticle is an efficient and innovative treatment for chronic inflammatory states such as diabetic foot ulcers.