Tissue‐Conforming Organoselenium Hydrogel with Microphase‐Controlled Acylhydrazone Crosslinking Kinetics Expedites Diabetic Wound Healing by Inhibiting AGE‐RAGE Pathways

Abstract

ABSTRACT Diabetic wounds present a pressing clinical challenge due to their self‐perpetuating pathological microenvironment, where oxidative stress, the accumulation of advanced glycation end‐products and their receptors (AGE‐RAGE), and chronic inflammation form a vicious cycle that impedes healing. The effective delivery of therapeutic agents by existing antioxidant hydrogels is compromised by their poor conformability to complex wound geometries due to rapid crosslinking kinetics, resulting in the failure to correct these interconnected pathological processes. Here, we synthesize an organoselenium polymer (OSP) capable of microphase‐separation to extend acylhydrazone crosslinking kinetics, thereby producing a tissue‐conforming organoselenium hydrogel (TCOH) that effectively presents organoselenium motifs to the pathological diabetic wound bed. The TCOH can effectively restore redox homeostasis, enhance angiogenesis, and reprogram the immune microenvironment by promoting M2 macrophage polarization. Transcriptomic profiling and Western Blot analyses concurrently confirm the restoration of glycolipid metabolism and suppression of AGE‐RAGE and NF‐κB signaling. This multifaceted restoration of the pro‐healing microenvironment results in accelerated wound closure, enhanced collagen deposition, and functional tissue regeneration. Our work establishes a new paradigm in chronic wound management by integrating dynamic material adaptation with multi‐targeted pathological regulation, offering a promising therapeutic platform for various redox‐ and AGE‐related chronic diseases.