Targeting Golgi–STING Signaling to Reprogram Innate and Adaptive Immunity for the Treatment of Implant‐Associated Infections

ABSTRACT Implant‐associated infections (IAIs) remain a significant clinical challenge due to the persistence of biofilms and the immunosuppressive microenvironment. This study presents a neutrophil‐hitchhiking ultrasound (US)‐driven nanoplatform (CS‐BT@MZ@NEs) designed to target Golgi pH modulation, activate immune pathways, and enhance antibacterial efficacy. The nanoplatform leverages neutrophil migration to cross the bone marrow–blood barrier and precisely deliver to deep infection sites. At the infection site, CS‐BT@MZ@NEs disrupts bacterial biofilms via US‐driven effects and modulates Golgi pH to activate the STING pathway. Golgi acidification promotes STING oligomerization and TBK1 activation, driving the release of interferons and pro‐inflammatory cytokines, which enhance macrophage M1 polarization, dendritic cell maturation, and T‐cell activation. In vivo, CS‐BT@MZ@NEs significantly reduced bacterial burden, suppressed myeloid‐derived suppressor cell infiltration, and increased CD4 ⁺ and CD8 ⁺ T‐cell responses. Furthermore, the nanoplatform induced robust immune memory, characterized by expanded memory T‐cell pools and elevated IgG levels, effectively preventing reinfection. Importantly, CS‐BT@MZ@NEs showed no systemic toxicity. These findings highlight CS‐BT@MZ@NEs as a novel therapeutic platform that integrates targeted delivery, Golgi pH modulation, and immune memory activation, offering a promising solution for IAIs treatment and advancing the field of nano‐immunotherapy.