An intelligent bacterial capture nanodrug enhances immunotherapy for implant-associated infections by inducing cuproptosis-like death in bacteria

Implant-associated infections (IAIs), particularly those involving methicillin-resistant Staphylococcus aureus (MRSA), present a major clinical challenge due to bacterial biofilm formation and localized immunosuppression. To address this, we developed an intelligent bacterial-capture nanodrug, termed Se-MPDA-Cu-D, designed to enhance immunotherapy through a synergistic antibacterial strategy. This nanoplatform features surface-modified D-alanine for targeted binding to bacterial peptidoglycan, enabling precise localization at infection sites. Within the acidic, glutathione-rich biofilm microenvironment, the nanodrug responsively releases copper ions (Cu 2+ ) and selenium nanoparticles (Se NPs), triggering a potent chemodynamic therapy that disrupts redox homeostasis and induces a cuproptosis-like death in bacteria. This process is characterized by copper accumulation, lipid peroxidation, DNA damage, and impairment of iron‑sulfur cluster proteins. Beyond its direct antibacterial efficacy, the treatment promotes a robust Immunogenic Bacterial Death (IBD) response, activating dendritic cells, enhancing T-cell infiltration, and reversing the immunosuppressive microenvironment. Furthermore, the released bioactive ions significantly promoted osteogenic differentiation and angiogenesis in vitro. In a rat model of MRSA-infected IAIs, Se-MPDA-Cu-D NPs effectively eradicated biofilms, facilitated substantial new bone regeneration, and restored osseointegration. This multifunctional nanotherapeutic approach presents a promising strategy for combating resistant implant infections by integrating targeted bacterial capture, cuproptosis-like death, and IBD.