Coordination-Driven Programming of MOF Stability for Hypoxia-Relieving Sonodynamic Therapy

Zr-based metal–organic frameworks (MOFs) are promising nanomedicine platforms, yet their rapid degradation in phosphate-rich biological environments remains a critical barrier to clinical translation. Here, we show that incorporating MnOx into PCN-224, a porphyrinic Zr-MOF, programmatically modulates the coordination environment of Zr6 clusters and suppresses phosphate-induced linker displacement, substantially extending structural integrity under physiological conditions. MnOx loading ratios systematically tune the degradation kinetics, with an optimized 1:1 MnOx@PCN-224 formulation retaining framework crystallinity in phosphate-buffered saline where bare PCN-224 undergoes complete disintegration within hours. Beyond structural stabilization, MnOx serves a dual therapeutic function as a catalase mimic, decomposing endogenous H2O2 into O2 to relieve tumor hypoxia and thereby potentiate sonodynamic therapy (SDT). Under high-intensity focused ultrasound (HIFU) irradiation, the stabilized porphyrin linkers generate markedly enhanced 1O2 levels compared to unmodified PCN-224. The nanoplatform, further coated with a GST-EGFR protein corona for tumor-targeted delivery, demonstrates significant tumor growth suppression in a 4T1 xenograft mouse model. This coordination-driven strategy transforms the inherent lability of Zr-MOFs from a limitation into a designable parameter, offering a generalizable approach to engineering MOF stability for in vivo therapeutic applications.