Hyperoside-based self-assembled hydrogel for modulating osteoimmune microenvironment to combat bacterial infections and facilitate bone repair

Infected bone defects (IBDs), primarily caused by Methicillin-resistant Staphylococcus aureus (MRSA), remain a major clinical challenge due to persistent bacterial colonization, dysregulated immune responses, and disruption of the osteogenic microenvironment. Here, a multifunctional hydrogel system composed of Gelatin methacryloyl (GelMA) and hyperoside (Hyp), Zn 2+ , Indocyanine green (ICG) self-assembled nanoparticles was developed to achieve a synergistic “antibacterial-immunomodulatory-osteogenic” therapeutic cascade. Upon near-infrared (NIR)-triggered photothermal therapy (PTT), the Hyp/Zn/ICG nanoparticles exhibited potent antibacterial activity against MRSA. Transcriptomic analysis revealed that PTT treatment disrupted bacterial ribosome assembly and protein synthesis pathways, leading to downregulation of MRSA resistance genes. Simultaneously, PTT-assisted therapy promoted macrophage M2 polarization and suppressed M1 polarization, thereby remodeling the osteoimmune microenvironment. Furthermore, the system enhanced osteogenic differentiation by upregulating RUNX2, COL1A1, and OPN, increasing alkaline phosphatase activity, and promoting matrix mineralization through the BMP signaling. In vivo , PTT-assisted treatment effectively eradicated MRSA, induced M2 polarization, and accelerated bone regeneration in infected bone defects. Collectively, this work introduces a safe, antibiotic-free therapeutic strategy for IBDs, leveraging a coordinated antibacterial, immunomodulatory, and osteogenic mechanism for efficient infection control and bone tissue repair.