Glutathione-Responsive Metal–Organic-Framework-Derived MnxOy/(A/R)TiO2 Nanoparticles for Enhanced Synergistic Sonodynamic/Chemodynamic/Immunotherapy

Despite the potential of sonodynamic therapy (SDT) in treating malignant tumors, the lack of effective sonosensitizers has limited its clinical implementation. In this study, we explored the relationship between the heteroatom doping concentration in metal–organic frameworks and interface formation after pyrolysis by regulating the addition of manganese sources and successfully derived Z-scheme heterojunctions MnxOy/(A/R)TiO2 (MTO) in situ from MIL-125-NH2 (Ti/Mn). The electron transfer pathway introduced by interfacial contact promoted carrier separation and greatly preserved the effective redox components, significantly influencing the performance of reactive oxygen species generation. Upon reaching the tumor sites, MTO effectively depleted glutathione to alleviate the suppressive tumor environment, and the heterojunctions and MnxOy in MTO facilitated SDT and synergistic chemodynamic therapy (CDT), respectively, leading to enhanced immunogenic cell death (ICD). Furthermore, Mn2+ uptake by dendritic cells (DCs) and the tumor-associated antigens released due to ICD activated the stimulator of interferon genes pathway, which elicited a robust tumor-specific immune response by driving the maturation of DCs and the activation of T cells. In addition, the activated T cells secreted high levels of interferon-γ to enhance Mn3+/Mn2+-mediated ferroptosis in metastatic tumor cells. The combination of MTO-mediated synergistic therapy and PD-L1 checkpoint blockade exhibited vaccine-like functions, inducing stronger systemic immunity and durable immune memory to inhibit tumor progression, metastasis, and recurrence. To summarize, we synthesized a self-enhancing nanoplatform for synergistic SDT/CDT/immunotherapy using multifunctional MOF-derived Z-scheme heterojunctions. This study provides an experimental basis for amplifying the potential of sonosensitizers while optimizing SDT-mediated systemic immunity while avoiding interference caused by additional adjuvants.