线粒体基质中H + /Ca 2+梯度的重新调节可以有效诱导线粒体去极化，从而增强癌症治疗。然而，它仍然面临着H +稳态、Ca 2+不足、不协调的调控和低效的装载/传递策略的挑战。在此，制备了超分子DNA纳米复合物（Ca@DNA–MF）来协同调节H + /Ca 2+梯度以实现线粒体去极化。通过靶向功能化和 TME 触发递送，癌细胞中释放多种试剂，实现协同三通道线粒体去极化：siMCT4 基因试剂通过下调单羧酸转运蛋白 4 (MCT4) 阻断 LA 代谢，诱导线粒体酸化；释放的Ca 2+破坏了Ca 2+稳态，促进基于Ca 2+的线粒体去极化；具体来说，TME 激活的谷胱甘肽 (GSH) 消耗促进了羟基自由基 (˙OH) 的有效生成，进一步增强了线粒体去极化。这种重新调节不仅引发细胞凋亡，还导致铁死亡，产生丰富的ROS，实现基于LPO的有效细胞凋亡，为增强协同癌症治疗提供了协同策略。
Synergistically remodulating H+/Ca2+ gradients to induce mitochondrial depolarization for enhanced synergistic cancer therapy
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.
