Synergistically remodulating H+/Ca2+ gradients to induce mitochondrial depolarization for enhanced synergistic cancer therapy

Abstract

The remodulation of H⁺/Ca²⁺ 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 Ca²⁺, uncoordinated regulations, and inefficient loading/delivery strategies. Herein, a supramolecular DNA nanocomplex (Ca@DNA–MF) was prepared to synergistically remodulate H⁺/Ca²⁺ 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 Ca²⁺ disrupted Ca²⁺ homeostasis to facilitate Ca²⁺-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.