Novel injectable polypeptide nanoparticle encapsulated siRNA targeting TGF‐β1 and COX‐2 for localized fat reduction I: Preclinical in vitro and animal models

Abstract Background Obesity and localized fat accumulation continue to drive the demand for minimally invasive body contouring technologies including injectable compounds for local fat reduction. siRNA offers a potential for an injectable to specifically target and silence genes involved in adipogenesis with minimal inflammatory side effects. Aims This study evaluates the efficacy of STP705, an injectable containing siRNA encapsulated within histidine‐lysine polypeptide (HKP) nanoparticles targeting transforming growth factor β1 (TGF‐β1) and cyclooxygenase‐2 (COX‐2), crucial mediators in adipocyte differentiation and fat retention, using in vitro, porcine, and murine models. Methods In vitro experiments on mouse preadipocytes and in vivo trials using Diet Induced Obese (DIO) mice and Yucatan minipigs were conducted to assess the gene silencing efficiency, tissue localization, pharmacodynamics, and safety profile of STP705. Results STP705 effectively reduced the expression of TGF‐β1 and COX‐2, with a notable decrease in adipocyte volume and lipid content without adverse systemic effects. In DIO mice, the HKP‐siRNA complex demonstrated precise localization to injected adipose tissue, maintaining significant gene silencing, and detectable levels of siRNA for up to 14 days post‐administration. Similar results in minipigs showed a significant reduction in subcutaneous adipose tissue thickness. Conclusion The results of these studies support the use of targeted siRNA therapy specifically targeting TGF‐β1 and COX‐2, for localized fat reduction, offering a potential minimally invasive alternative to current fat reduction methods.