A Biomimetic Multistage RNAi Platform Restores Mitochondrial Function in Diabetic Wounds via the ALKBH5‐m ⁶ A‐C2orf69 Axis

ABSTRACT

Diabetic wounds remain a major clinical challenge, largely due to vascular dysfunction. Here, we identified a previously unrecognized N ⁶ ‐methyladenosine (m ⁶ A)‐dependent mechanism underlying endothelial injury in diabetic wounds. The m ⁶ A demethylase ALKBH5 was upregulated in diabetic wound endothelium, leading to reduced m ⁶ A modification within the coding sequence (CDS) of C2orf69 mRNA. Loss of m ⁶ A weakened IGF2BP2‐mediated stabilization of C2orf69 transcripts, resulting in decreased C2orf69 expression, mitochondrial dysfunction, and impaired angiogenesis. To therapeutically target the ALKBH5‐m ⁶ A‐C2orf69 axis, we developed a biomimetic membrane‐fusion nanovesicle system (siALK@L‐Hyb) integrating arginine‐rich lipopeptides (A‐LPs), endothelial cell membranes, milk‐derived extracellular vesicles (mEVs), and ALKBH5‐specific siRNA. This platform enhanced tissue penetration, promoted endothelial uptake, and facilitated lysosomal escape, thereby achieving a sequential “Tissue‐Cell‐Organelle” intervention. The resulting efficient delivery of ALKBH5 siRNA restored mitochondrial function, improved angiogenesis, and significantly accelerated diabetic wound healing. Our work not only uncovers a novel m ⁶ A‐regulated endothelial injury pathway in diabetic wounds, but also presents a versatile and translational nanoplatform for RNAi‐based therapy.