Ultra-Stable MOF@MOF Nanoplatform for Photodynamic Therapy Sensitized by Relieved Hypoxia due to Mitochondrial Respiration Inhibition.

Metal-organic frameworks (MOFs) with periodically arranged porphyrinic linkers avoiding the self-quenching issue of porphyrins in photodynamic therapy (PDT) have been widely applied. However, the porphyrinic MOFs still face challenges of poor stability under physiological conditions and limited photodynamic efficiency by the hypoxia condition of tumors. Herein, we fabricate the MOF@MOF structure with a protective MOF shell to improve the stability and relieve the hypoxia condition of tumors for sensitized PDT. Under protection of the MOF shell, the MOF@MOF structure can keep intact for 96 hours under physiological conditions. Consequently, the tumoral accumulation efficiency is two folds of the MOF core. Furthermore, the MOF shell decomposes under acidic environment, and the loaded inhibitor of mitochondria pyruvate carrier (7-amino carboxycoumarins-2, 7ACC2) will be released. 7ACC2 inhibits the mitochondrial pyruvate influx and simultaneously blocks glucose and lactate from fueling the mitochondrial respiration, thereupon relieving the hypoxia condition of tumors. Under a 5-min laser irradiation, the 7ACC2 carrying MOF@MOF nanoplatforms induced doubled cellular apoptosis and reduced 70% of the tumor growth compared with the cargo-free MOF@MOF. In summary, the design of this stable and hypoxia self-relievable MOF@MOF nanoplatform will enlighten the future development of MOF-based nanomedicines and PDT. STATEMENT OF SIGNIFICANCE: : Porphyrinic metal-organic frameworks (MOFs) have been widely applied in photodynamic therapy (PDT) as a kind of superior nano-photosensitizers. However, they still face challenges in poor stability under physiological conditions and limited photodynamic efficiency due to the hypoxia condition of tumors. In order to solve these problems, (1) we developed a MOF@MOF strategy to improve the physiological stability; (2) an inhibitor of mitochondria pyruvate carrier, 7-amino carboxycoumarins-2 (7ACC2), was loaded to inhibit the mitochondrial pyruvate influx and simultaneously block glucose and lactate from fueling the mitochondrial respiration, thereupon relieving the hypoxia condition of tumors. The design of this stable and hypoxia self-relievable MOF@MOF nanoplatform will enlighten the future development of MOF-based nanomedicines and PDT.