A Mitochondria‐Driven Metabolic Sensing Nanosystem for Oxygen Availability and Energy Blockade of Cancer

A mitochondrial targeting and adenosine triphosphate (ATP)‐responsive nanosystem is designed and constructed to interfere with mitochondrial respiration. This triggers metabolic therapy and enhanced photodynamic therapy of malignant tumor via blocking of ATP and the diversion of endogenous oxygen. The nanosystem is synthesized by incorporating the drug resveratrol (RES) into porous coordination polymer PCN‐224 (RES@PCN). After RES@PCN nanoparticles target the tumor site by enhanced penetration and retention (EPR) effects, PCN delivery endows RES@PCN nanoparticles with the ability to target mitochondria. Subsequently, ATP overexpressed in the mitochondria of tumor cell disintegrates the PCN structure by coordination substitution. This also leads to release of entrapped drug RES. As an ATPase inhibitor, RES interferes with the metabolism of the respiratory chain of tumor cell, triggering an ATP‐blocked metabolic therapy. In addition, inhibition of mitochondrial respiration reduces the consumption of endogenous oxygen. The spare oxygen is used as an “oxygen depot” in photodynamic therapy for generation of toxic reactive oxygen species. Taken together, the mitochondria‐driven metabolic interference system successfully achieves synergistic photodynamic and metabolic therapy via a respiratory inhibition‐medicated oxygen diversion and an ATP blockade. This strategy has great potential for cancer treatment.