Targeting Golgi-STING Signaling to Reprogram Innate and Adaptive Immunity for the Treatment of Implant-Associated...

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.