Synergistically remodulating H(+)/Ca(2+) gradients to induce mitochondrial depolarization for enhanced synergistic cancer therapy

The remodulation of H(+)/Ca(2+) gradients in the mitochondria matrix could be effective to induce mitochondria depolarization for the enhancement of cancer therapy. However, it is still challenged by H(+) homeostasis, insufficient Ca(2+), uncoordinated regulations, and inefficient loading/delivery strategies. Herein, a supramolecular DNA nanocomplex (Ca@DNA–MF) was prepared to synergistically remodulate H(+)/Ca(2+) gradients for mitochondrial depolarization. Upon targeted functionalization and TME-triggered delivery, multiple reagents were released in cancer cells for synergistic three-channel mitochondrial depolarization: the gene reagent of siMCT4 blocked the LA metabolism to induce mitochondrial acidification by downregulating monocarboxylate transporter 4 (MCT4); released Ca(2+) disrupted Ca(2+) homeostasis to facilitate Ca(2+)-based mitochondrial depolarization; specifically, TME-activated glutathione (GSH) depletion facilitated efficient generation of hydroxyl radicals (˙OH), further enhancing the mitochondrial depolarization. The remodulation not only triggered apoptosis but also led to ferroptosis to generate abundant ROS for efficient LPO-based apoptosis, providing a synergistic strategy for enhanced synergistic cancer therapy.