Bioresponsive Nar‐Zn@GelMA Hydrogel Reprograms the Diabetic Wound Microenvironment via Antioxidant and Immunoregulatory Synergy

Abstract

Abstract Chronic diabetic wounds (DWs) exhibit persistent inflammation, oxidative stress, and dysregulated macrophage polarization, forming a hostile microenvironment that compromises tissue repair. To address these multifactorial barriers, a multifunctional bioresponsive hydrogel (Nar‐Zn@GelMA) is designed. GelMA is photopolymerized as the primary network and further crosslinked with Benzaldehyde‐PEG‐Benzaldehyde (DF‐PEG‐DF) via dynamic Schiff base reactions, creating a reversible network, while naringenin (Nar) and zinc ions (Zn 2 ⁺) endowed antioxidative and immunoregulatory functionalities. The hydrogel demonstrated robust gelation, structural integrity, and favorable cytocompatibility and tissue integration. In vitro, Nar‐Zn@GelMA scavenged intracellular reactive oxygen species (ROS), alleviated oxidative stress, and reprogrammed RAW264.7 macrophages toward an M2 phenotype, underscoring its strong immunoregulatory potential. In streptozotocin‐induced diabetic mice, topical hydrogel application promoted wound closure and significantly improved re‐epithelialization, collagen remodeling, and neovascularization. Proteomic analysis reveals upregulation of key proteins (Hspa1l, Prdx1, Tlr2) involved in immune modulation, inflammatory resolution, and Toll‐like receptor signaling, indicative of a synergistic mechanism for microenvironment reprogramming. Histological and biosafety assessments validated excellent tissue integration and systemic compatibility. Collectively, Nar‐Zn@GelMA represents a structurally and therapeutically integrated platform offering a robust strategy for chronic diabetic wound regeneration.