Lung-targeted feedback regulation of mitochondrial ATP synthetic pathway for orthotopic tumors suppression

Abundant adenosine triphosphate (ATP), an important mediator of metabolic reprogramming in cancer progression, is regarded as a significant focus in cancer treatment. Nonetheless, due to low selectivity, the attempts of ATP exhaustion may induce unacceptable side effects because ATP also plays key roles in maintaining normal cell function. Inspired by feedback inhibition in nature, here, we propose feedback inhibition of mitochondrial ATP synthetic pathway for tumors inhibition while minimizing side effects. As a proof-of-concept, an ATP-responsive ZIF-90 as a broad framework for mitochondrial-targeted delivery of 2, 2’-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) and an FDA-approved drug bedaquiline (BE). It was found that ZIF-90/AIPH/BE nanocomplex exhibits unique properties of high pulmonary accumulation and mitochondria-targeting capability. When ATP is present, the ZIF-90/AIPH/BE nanoparticles were eroded and release the wrapped contents because of the competitive binding between ATP and the Zn2+ in ZIF-90. The released AIPH and BE significantly reduced ATP-production, causing mitochondrial ATP depletion. The reduced ATP restricted the follow-up release of ZIF-90/AIPH/BE nanocomplex in a negative-feedback manner. The feedback inhibition mechanism expands the possibilities for targeted disease treatment and opens up new avenues for ATP-based nanomedicine.