Ultrasmall Manganese-Doped TiO2–x Overcomes the Efficacy–Safety Dilemma of Sonodynamic Therapy via Tumor Microenvironment-Responsive Reactive Oxygen Species Amplification and Clearance

The clinical translation of inorganic sonosensitizers for cancer sonodynamic therapy (SDT) is constrained by two interconnected barriers: insufficient therapeutic efficacy due to low reactive oxygen species (ROS) yield and long-term toxicity risks due to poor metabolic clearance. Although conventional ultrasmall size designs achieved renal clearance, they reduce the sonosensitizers’ accumulation in the tumor and further weaken treatment outcomes. To address these challenges, we developed a tumor microenvironment (TME)-responsive Mn-doped TiO2–x nanoplatform (2.4 nm). Optimal Mn doping induced defect-mediated bandgap narrowing, generating oxygen vacancies and intermediate states that reduced the TiO2 bandgap from 3.20 to 2.30 eV, thereby enhancing sonosensitivity. Simultaneously, Mn2+-driven Fenton-like catalysis exploited elevated H2O2 levels to generate O2 in the TME, alleviating tumor hypoxia while amplifying ROS production. Critically, pH-triggered surface transformation enabled spontaneous intratumoral aggregation: acid-labile PEG shedding exposed biorthogonal click groups that cross-link sonosensitizers into ∼230 nm assemblies, thereby boosting tumor retention. This integrated strategy elevated cellular ROS yield 9.7-fold under ultrasound irradiation and achieved 98.2% tumor suppression in mouse models. Concurrently, nonaccumulated sonosensitizers were cleared by the kidney due to their ultrasmall diameter, mitigating systemic toxicity risks. This work establishes a paradigm for inorganic sonosensitizers that intrinsically unite defect-optimized sonosensitivity, TME-enhanced catalysis, and tumor-retentive aggregation with on-demand metabolic clearance, resolving the fundamental efficacy–safety conflict in SDT.