An All‐Natural Multifunctional Hydrogel Incorporating Carrier‐Free Self‐Assembled Microparticles for the Treatment of S. aureus ‐Infected Wounds

ABSTRACT Multifunctional wound dressings combining antibacterial activity and tissue regeneration are highly desirable for infected wound management. In this study, a multifunctional chitosan‐gelatin hydrogel incorporating carrier‐free self‐assembled anisaldehyde‐tannic acid‐Zn 2 + (AA‐TA‐Zn 2 + ) bioactive microparticles is developed. These microparticles are fabricated through non‐covalent self‐assembly and metal‐phenolic coordination without additional polymeric carriers or surfactants. Anisaldehyde (AA) serves as both an antibacterial agent and a hydrophobic structural building block, while tannic acid (TA) and Zn 2 + provide complementary antioxidant and coordination functions. Incorporation of these microparticles into the chitosan‐gelatin matrix enhances the structural integrity and multifunctionality of the resulting composite hydrogel through dynamic intermolecular interactions. The hydrogel exhibits excellent injectability, self‐healing capability, tissue adhesion, and sustained release with pH‐responsive behavior. In vitro experiments demonstrate the antibacterial, antioxidant, and anti‐inflammatory activities of the microparticles and composite hydrogel, including their ability to alleviate oxidative stress and inflammatory responses, as well as the hydrogel's effectiveness in disrupting established Staphylococcus aureus biofilms. In a murine model of S. aureus ‐infected wounds, the hydrogel significantly accelerates wound closure and enhances collagen deposition and tissue restoration. This study presents a promising strategy for integrating carrier‐free bioactive microparticles into a natural biopolymer hydrogel matrix, offering a multifunctional platform for infected wound management.