Enhanced Chemoradiotherapy for MRSA‐Infected Osteomyelitis Using Immunomodulatory Polymer‐Reinforced Nanotherapeutics

Abstract The eradication of osteomyelitis caused by methicillin‐resistant Staphylococcus aureus (MRSA) poses a significant challenge due to its development of biofilm‐induced antibiotic resistance and impaired innate immunity, which often leads to frequent surgical failure. Here, the design, synthesis, and performance of X‐ray‐activated polymer‐reinforced nanotherapeutics that modulate the immunological properties of infectious microenvironments to enhance chemoradiotherapy against multidrug‐resistant bacterial deep‐tissue infections are reported. Upon X‐ray radiation, the proposed polymer‐reinforced nanotherapeutic generates reactive oxygen species and reactive nitrogen species. To robustly eradicate MRSA biofilms at deep infection sites, these species can specifically bind to MRSA and penetrate biofilms for enhanced chemoradiotherapy treatment. X‐ray‐activated nanotherapeutics modulate the innate immunity of macrophages to prevent the recurrence of osteomyelitis. The remarkable anti‐infection effects of these nanotherapeutics are validated using a rat osteomyelitis model. This study demonstrates the significant potential of a synergistic chemoradiotherapy and immunotherapy method for treating MRSA biofilm‐infected osteomyelitis.