<p>Diabetic foot ulcer (DFU), a severe complication of diabetes, results from neuronal damage caused by hyperglycemia and the accumulation of advanced glycation end products in the vascular endothelium. This impairs blood flow, hindering the wound healing process from the inflammatory to the proliferative phase. Current therapeutic strategies, including the use of growth factors and biomarkers, face significant pitfalls such as rapid clearance by wound exudates and limited penetration into the wound. To overcome these challenges, gene-level targeting strategies, such as small interfering RNA (siRNA), are being explored for their potential to address the underlying causes of chronic wounds. However, siRNA delivery faces several hurdles, including serum instability, uptake by the reticuloendothelial system (RES), and inefficient endosomal escape. The present article delves into the potential of siRNA in the management of chronic diabetic wounds, elaborating on the challenges of its skin delivery and offering nano-based strategies as potential solutions. Additionally, a discussion on the limitations of nanocarriers and the regulatory considerations associated with their development has been provided. This comprehensive overview aims to provide insights into the utility of siRNA for DFUs and inspire advancements in gene-based wound therapies.</p> Graphical Abstract <p></p>