Injectable hydrogels for osteomyelitis treatment induce metabolic reprogramming for protection against reinfection

Osteomyelitis, especially multidrug-resistant cases, remains a formidable clinical challenge due to recurrent infections and antibiotic limitations. Here, we present an injectable GaCuVan&HACHO-BSA hydrogel that self-assembles in situ within the bone marrow cavity—the epicenter of trained immunity—to simultaneously eradicate pathogens, induce innate immune memory, and regenerate bone. The hydrogel captured bacteria, virulence factors, and inflammatory mediators through multivalent interactions with enhanced injectability, biocompatibility, and sustained antigen release, making it ideal for minimally invasive treatment of osteomyelitis-related bone defects. Mechanistically, adsorbed pathogen signatures activated pattern recognition receptors, triggering metabolic reprogramming (elevated succinate/ATP/lactate), HIF-1α stabilization, amplified glycolysis and inflammation (COX2/iNOS/CD86), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) production—collectively inducing trained immunity with cross-protection against homologous/heterologous reinfection. Furthermore, glycyrrhizic acid promoted bone tissue repair and modulated immune responses. By converging antimicrobial defense, innate immune memory, and tissue repair into a single platform, this work redefines osteomyelitis management and advances immunomodulatory biomaterials for clinical translation. Here, Chen et al. develop an injectable hydrogel that induces innate immune memory against reinfection and promotes bone repair in osteomyelitis, offering a biomaterial-based immunomodulatory strategy for refractory bone infections.