A Multifunctional Tissue‐Engineering Hydrogel Aimed to Regulate Bacterial Ferroptosis‐Like Death and Overcoming Infection Toward Bone Remodeling

Infection is the most common complication after orthopedic surgery and can result in prolonged ailments such as chronic wounds, enlarged bone defects, and osteomyelitis. Iron, which is essential for bacterial metabolism and immune cell functions, is extremely important. Bacteria harness iron from nearby cells to promote biofilm formation, ensuring their survival. Iron deficiency within the infection microenvironment (IME) consequently hampers macrophage function, enabling further dissemination of the infection and hindering macrophage polarization to the M2 phenotype. Therefore, a novel approach is proposed to regulate macrophage polarization, aiming to restore the inflammatory immune environment. A composite hydrogel derived from natural polymers is developed to address infections and manage iron metabolism in macrophages. This IME‐responsive hydrogel, named FCL‐ECMH, is synthesized by encapsulating vermiculite functional core layers within a decellularized extracellular matrix hydrogel. It is noteworthy that FCL‐ECMH can produce reactive oxygen species within the IME. Supplementary photothermal treatment enhances bacterial iron uptake, leading to ferroptosis‐like death. This process also rejuvenates the iron‐enriched macrophages around the IME, thereby enhancing their antibacterial and tissue repair functions. In vivo experiments confirmed the antibacterial and repair‐promoting capabilities of FCL‐ECMH, indicating its potential for clinical applications. Herein, a multifunctional tissue‐engineering hydrogel (FCL‐ECMH) is presented for the treatment of tissue infection using a novel dual approach strategy involving promoting bacterial ferroptosis‐like death and regulating macrophage polarization. The synergistic effect contributes to the outstanding therapeutic efficacy of FCL‐ECMH against musculoskeletal infections, providing a new option for the clinical treatment of refractory musculoskeletal infections.