Bioactive Granular Hydrogels for Infection Control and Immune Microenvironment Remodeling in Wound Regeneration

Bacterial infection remains a major barrier to effective wound healing by disrupting immune homeostasis, sustaining chronic inflammation, and impairing tissue regeneration. Herein, we present a green, sustainable strategy for fabricating antibacterial, immunomodulatory bioactive granular hydrogels (GHs) for infected wound regeneration. An amino-alcohol ether prepolymer (MP) was first synthesized via epoxy–amine click chemistry and subsequently complexed with the natural polyphenol tannic acid (TA), thereby triggering phase-separation-driven supramolecular self-assembly into GHs without additional crosslinkers. To elucidate the polymer assembly mechanism and identify the bioactive concentration threshold, agarose was introduced as a fourth component to construct A/MP@TA GHs. The results showed that increasing the agarose content progressively transformed the granular architecture into a sheet-like network, whereas A/MP@TA3, which represents the lowest agarose ratio that preserves the granular morphology, exhibited potent antibacterial and antioxidant activities, and enhanced fibroblast migration. In a bacteria-infected wound, A/MP@TA3 still markedly accelerated wound closure while promoting collagen deposition and angiogenesis. Mechanistically, sustained TA release reprogrammed the microenvironment by activating the KEAP1/Nrf2/HO-1 and suppressing NF-κB signaling, thereby driving macrophage polarization toward a pro-regenerative M2 phenotype. This work establishes a simple, cost-effective, and environmentally friendly platform for fabricating multifunctional hydrogel dressings and provides a biomaterial-based strategy for remodeling the immune microenvironment.