Self-Reinforcing Nanosonosensitizer Boosts Cascade Immune Activation for Refractory Osteomyelitis Treatment and Recurrence Prevention

Osteomyelitis, most commonly caused by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), remains a formidable clinical challenge due to its chronic progression, immune evasion mechanisms, and resistance to conventional antibiotics. To overcome these barriers, we developed a multifunctional nanoplatform (TMZ) that integrates targeted bacterial eradication with localized immune activation. Trehalose functionalization confers selective recognition of MRSA, thereby enhancing bacterial targeting efficiency. Upon ultrasound irradiation, TMZ generates reactive oxygen species that compromise bacterial membranes and induce immunogenic bacterial death, leading to the release of bacterial DNA and antigens. Concurrently, TMZ undergoes pH-responsive degradation within the acidic osteomyelitis microenvironment, resulting in the controlled release of Mn²⁺ ions. These ions act synergistically with bacterial components to activate the cyclic GMP-AMP synthase-stimulator of interferon gene pathway in dendritic cells, thereby promoting innate immune activation, dendritic cell maturation, and efficient antigen presentation. This immune cascade further elicits pathogen-specific adaptive responses and establishes durable immunological memory. <i>In vitro</i> studies showed TMZ exhibited potent bactericidal activity against both planktonic MRSA and mature biofilms. In a murine model of MRSA-induced osteomyelitis, TMZ markedly reduced bacterial burden, activated systemic antibacterial immunity, prevented recurrence, and outperformed conventional antibiotics without inducing resistance. Overall, this work introduces a closed-loop sonodynamic-immune nanotherapy that couples precision bacterial eradication with robust immune activation, offering a promising therapeutic strategy for refractory osteomyelitis and providing new insights into nanomedicine-based immunotherapies for deep-seated bacterial infections.