A Tissue-Homologous Keratin-PBA Hydrogel Integrating Rationally Designed Nanomicelles Enables Microenvironment-Adaptive Repair of Chronic Diabetic Wounds.

Abstract

Chronic diabetic wounds require continuous modulation of the hyperglycemia-induced pathological microenvironment. Although glucose-responsive biomaterials show promise for diabetic wound treatment, intelligent wound management with tissue specificity and multifactorial repair capacity remains urgently needed. Here, we develop a tissue-homologous, glucose-responsive hydrogel based on epidermis-derived keratin functionalized with phenylboronic acid (Keratin-PBA), which is crosslinked with oxidized sodium alginate (OSA) to form a double-network hydrogel (cOK) and integrated with bioactive nanomicelles for adaptive wound microenvironment regulation. Co-assembled nanomicelles (OA-PG NMs), composed of oleanolic acid (OA) and propyl gallate (PG), exhibit glucose-triggered release and complementary bioactivities targeting oxidative stress, inflammation, macrophage polarization, angiogenesis, fibroblast behavior, antibacterial activity, and MMP regulation. Notably, OA promotes angiogenesis via the TGR5-Akt-eNOS-NO signaling pathway. The resulting cOK@NM hydrogel enables spatiotemporally controlled nanomicelle release and significantly accelerates diabetic wound healing in vivo, as evidenced by rapid wound closure, enhanced M2 macrophage polarization, robust neovascularization, improved collagen remodeling, reduced AGEs, broad-spectrum antibacterial effects against E. coli and S. aureus, and increased granulation tissue formation. This work presents a tissue-homologous, intelligently adaptive platform integrating intrinsic regenerative bioactivity with glucose-responsive therapeutic adaptability.