Combined activation of artificial and natural ion channels for disrupting mitochondrial ion homeostasis towards effective postoperative tumor recurrence and metastasis suppression.

Rationale: Pharmacological targeting of mitochondrial ion channels is developing as a new direction in cancer therapy. The opening or closing of these channels can impact mitochondrial function and structure by interfering with intracellular ion homeostasis, thereby regulating cell fate. Nevertheless, their abnormal expression or regulation poses challenges in eliminating cancer cells, and further contributes to metastasis, recurrence, and drug resistance. Methods: We developed an engineered mitochondrial targeted delivery system with self-reinforcing potassium ion (K+) influx via amphiphilic mitochondrial targeting polymer (TMP) as carriers to co-deliver natural K+ channel agonists (Dinitrogen oxide, DZX) and artificial K+ channel molecules (5F8). Results: Using this method, DZX specifically activated natural K+ channels, whereas 5F8 assembled artificial K+ channels on the mitochondrial membrane, leading to mitochondrial K+ influx, as well as oxidative stress and activation of the mitochondrial apoptotic pathway. Conclusion: The synergistic effect of 5F8 and DZX presents greater effectiveness in killing cancer cells than DZX alone, and effectively inhibited tumor recurrence and lung metastasis following surgical resection of breast cancer tumors in animal models. This strategy innovatively integrates antihypertensive drugs with artificial ion channel molecules for the first time to effectively inhibit tumor recurrence and metastasis by disrupting intracellular ion homeostasis, which will provide a novel perspective for postoperative tumor therapy.