defective engineering, metal–organic frameworks, multiple antioxidant defenses, sonodynamic tumor therapy, Physics, QC1-999, Chemistry, QD1-999

Sonodynamic therapy has emerged as a spatiotemporally controllable therapeutic modality in combating triple‐negative breast cancer, yet the therapeutic efficiency of sonosensitizers is limited by the low energy conversion and endogenous antioxidant system. Herein, a defect‐engineered nano‐sonosensitizer (MVP@HA) is synthesized through in situ local etching deposition of vanadyl phosphate (VOPO4) onto the porous walls of zirconium‐based porphyrin metal–organic frameworks (MOFs). VOPO4 partially degraded under pathological environment can effectively inhibit the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) and its downstream antioxidant enzymes and antioxidant molecules. Concomitantly, autophagy process and glutathione production are impaired by cascaded inhibition and direct consumption, inducing multiple overcoming of cellular antioxidant defense. Moreover, the sonosensitive efficiency and catalytic oxidation efficiency of MOFs are enhanced by the generation of metal defects on porous and the etching‐expanded porous structures through promoting the mass transfer of substrate. The nano‐sonosensitizers show higher 1O2 yield (≈2.2‐fold) than MOFs and effective reduction of Nrf2 expression (2.8‐fold). Thereby, more effective inhibition of tumor growth is achieved compared to traditional porphyrin MOFs (3.45‐fold). This system significantly advances defect‐engineered nano‐sonosensitizers for tumor therapy.