Lung-targeted feedback regulation of the mitochondrial ATP synthesis pathway for orthotopic tumor suppression

Abundant adenosine triphosphate (ATP), an important mediator of metabolic reprogramming in cancer progression, is regarded as a significant target in cancer treatment. Nonetheless, due to low selectivity, attempts to exhaust ATP may induce undesirable side effects because ATP also plays key roles in maintaining normal cell function. Inspired by the feedback inhibition mechanism found in nature, we propose feedback inhibition of the mitochondrial ATP synthetic pathway for tumor inhibition with minimal side effects. As a proof-of-concept, an ATP-responsive ZIF-90 broad framework for the mitochondria-targeted delivery of 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) and an FDA-approved drug, bedaquiline (BE), is presented in this work. The ZIF-90/AIPH/BE nanocomplex exhibits unique properties, including high pulmonary accumulation and mitochondria-targeting capability. When ATP is present, the ZIF-90/AIPH/BE nanoparticles disintegrate and release the encapsulated molecules because of the competitive binding between ATP and Zn²⁺ present in ZIF-90. The released AIPH and BE significantly reduce ATP production, causing mitochondrial ATP depletion. The reduction in ATP acts as a negative feedback and restricts the subsequent release of the ZIF-90/AIPH/BE nanocomplex. The feedback inhibition mechanism expands the possibility of targeted disease treatment and opens up new avenues for ATP-based nanomedicine.