Multiresponsive β-Cyclodextrin-Modified Hyaluronic Acid Hydrogel Loaded with Cu-Zn Nanozymes for Accelerated Diabetic...

Diabetic wound healing remains a major clinical challenge driven by excessive reactive oxygen species (ROS) and persistent inflammation. Herein, we report a multifunctional responsive hydrogel (Glu@nano) engineered from a thiol-modified hyaluronic acid (C-HA) matrix. Phenylboronic acid-functionalized carboxymethyl-β-cyclodextrin was synthesized via amide coupling and subsequently integrated into C-HA through reversible boronate ester bonds formed between PBA and cis-diol motifs on the HA backbone, while partial oxidation of pendant thiols generated interchain disulfide crosslinks. These dual-dynamic interactions create a three-dimensional network responsive to both glucose and reducing microenvironments. Cu-Zn dual-atom nanozymes were further anchored within the scaffold via coordination with backbone carboxyl/amino groups, endowing the system with robust SOD-, CAT-, and POD-like catalytic activity for efficient ROS elimination. Upon topical application to diabetic wounds, Glu@nano demonstrated rapid wound contraction, suppressed pro-inflammatory IL-6, promoted angiogenesis and collagen deposition, and established a regenerative microenvironment conducive to healing. This work presents an innovative material-based strategy for concurrent targeting of multiple pathological hallmarks in diabetic wounds and holds substantial potential for clinical translation.