Ultrasmall Manganese-Doped TiO 2– x Overcomes the Efficacy–Safety Dilemma of Sonodynamic Therapy via Tumor Microenvironment-Responsive Reactive Oxygen Species Amplification and Clearance

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.