金属有机框架（MOFs）是一种周期性排列的卟啉连接剂，可以避免卟啉在光动力疗法（PDT）中的自熄灭问题，并得到广泛应用。然而，卟啉MOFs仍面临生理条件下稳定性差以及瘤内缺氧条件限制光动力疗法效率的挑战。在此，我们构建了一个保护性MOF壳层的MOF@MOF结构，以提高稳定性并缓解瘤内缺氧条件，从而用于敏化型PDT。在MOF壳层的保护下，MOF@MOF结构在生理条件下可以保持96小时的完整性。因此，肿瘤的堆积效率是MOF核心的两倍。此外，MOF壳层在酸性环境下会分解，载荷的线粒体丙酮酸载体抑制剂（7-氨基羧基香豆素-2，7ACC2）将被释放。7ACC2抑制线粒体丙酮酸流入，并同时阻断葡萄糖和乳酸为线粒体呼吸提供能源，从而缓解瘤内缺氧条件。在5分钟的激光照射下，携带7ACC2的MOF@MOF纳米平台引发了双倍的细胞凋亡，并与不携带药物的MOF@MOF相比，减少了70%的肿瘤生长。总之，这种稳定且自缓解缺氧的MOF@MOF纳米平台的设计将启发MOF基于纳米医药和光动力疗法的未来发展。重要性陈述：卟啉金属有机框架（MOFs）作为一种优秀的纳米光敏剂已得到广泛应用于光动力疗法（PDT）。然而，由于瘤内缺氧条件，它们仍然面临着生理条件下稳定性差以及光动力疗法效率有限的挑战。为了解决这些问题，我们开发了一种MOF@MOF策略来提高生理稳定性，并载入线粒体丙酮酸载体抑制剂7-氨基羧基香豆素-2（7ACC2），用于抑制线粒体丙酮酸流入并同时阻断葡萄糖和乳酸为线粒体呼吸提供能源，从而缓解瘤内缺氧条件。这种稳定且自缓解缺氧的MOF@MOF纳米平台的设计将启发MOF基于纳米医药和光动力疗法的未来发展。版权所有 © 2023 Elsevier Ltd. 发布。

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.Copyright © 2023. Published by Elsevier Ltd.