Background: Bacterial invasion, protracted inflammation, and angiogenesis inhibition are hallmarks of chronic diabetic wounds, bringing about patient morbidity and rising healthcare costs. For such wounds, there are currently few efficient therapies available. Methods: We reported the development of carboxymethyl chitosan (CMCS)-based self-healing hydrogel loaded with ultra-small copper nanoparticles (Cunps) for local treatment of diabetic wound healing. The structure of Cunps was identified by XRD, TEM, XPS and other methods, and the characterization of the synthesized Cunps-loaded self-healing carboxymethyl chitosan (CMCS)-protocatechualdehyde (PCA) hydrogel (Cunps@CMCS-PCA hydrogel) was further investigated. The therapeutic effect of Cunps@CMCS-PCA hydrogel in diabetic wound healing was explored in vitro and in vivo. Results:The findings showed that a kind of ultra-small size copper nanoparticles with excellent biocompatibility was prepared. CMCS was chemically conjugated to PCA to form self-healing hydrogels via the formation of an amide bond followed by the loading of ultra-small copper nanoparticles. The obtained Cunps@CMCS-PCA hydrogel showed a typical three-dimensional interlinked network structure with self-healing ability and porosity. It exhibited good biocompatibility in diabetic wounds. Furthermore, Cunps@CMCS-PCA hydrogel group significantly prevented bacterial growth in the skin wound of diabetic rats as compared to model group and CMCS-PCA hydrogel-treated group. After 3 days, no visible bacterial proliferation was observed. It also increased angiogenesis through Cunps mediated activation of ATP7A to prevent induction of autophagy. Furthermore, Cunps@CMCS-PCA hydrogel mainly depended on PCA-induced inhibition on inflammation of macrophage via JAK2/STAT3 signaling pathway. As a result, compared with delayed wound healing process with lower wound healing rate valued at 68.

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