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

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 (Zn²⁺) 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.