Multifunctional Injectable Microspheres Containing “Naturally-Derived” Photothermal Transducer for Synergistic Physical and Chemical Treating of Acute Osteomyelitis through Sequential Immunomodulation

Osteomyelitis induced by Staphylococcus aureus (S. aureus) is a persistent and deep-seated infection that affects bone tissue. The main challenges in treating osteomyelitis include antibiotic resistance, systemic toxicity, and the need for multiple recurrent surgeries. An ideal therapeutic strategy involves the development of materials that combine physical, chemical, and immunomodulatory synergistic effects. In this work, we prepared injectable microspheres consisting of an interpenetrating network of ionic-cross-linked sodium alginate (SA) and genipin (Gp)-cross-linked gelatin (Gel) incorporated with tannic acid (TA) and copper ions (Cu²⁺). The Gp-cross-linked Gel acted as a "naturally-derived" photothermal therapy (PTT) agent. The results showed that the microspheres exhibited efficient and rapid bactericidal effects against both S. aureus and Escherichia coli (E. coli) under the irradiation of near-infrared light at 808 nm wavelength; moreover, the release of Cu²⁺ also induced sustained inhibitory effects against bacteria during the nonirradiation period. The in vitro cell culture results indicated that when combined with PTT, the microspheres could adaptively modulate macrophage M1 and M2 phenotypes in sequence. Additionally, these microspheres were found to enhance the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In vivo studies conducted in a rat femur osteomyelitis model with bone defects showed that under multiple laser irradiation the microspheres effectively controlled bacterial infection, improved the pathological immune microenvironment, and significantly enhanced the repair and regeneration of bone tissues in the affected area.