Cascade specific endogenous Fe3+ interference and <i>in situ</i> catalysis for tumor therapy with stemness suppression

Cancer stem-like cells (CSCs), featuring high tumorigenicity and invasiveness, are one of the critical factors leading to the failure of clinical cancer treatment such as metastasis and recurrence. However, current strategies suffer from the low stemness-inhibiting efficacy on CSCs by conventional molecular agents and the poor lethal effects against bulk tumor cells. Here we engineer a coordination nanomedicine by 2,5-dihydroxyterephthalic acid (DHT) complexing zinc ions (Zn²⁺) as a double-effect nanodisrupter of tumor iron (Fe) and redox homeostasis for catalysis-boosted tumor therapy with stemness inhibition. Taking advantage of the much higher binding force of DHT toward Fe³⁺, this nanomedicine can specifically chelate endogenous Fe³⁺ into its nanostructure and release Zn²⁺, and the <i>in situ</i> formed hexacoordinated Fe-DHT conformation is of much enhanced reducibility in order to promote reactive oxygen species (ROS) production in tumors. The nanomedicine-mediated Fe depletion and ROS generation collectively induce CSC differentiation <i>via</i> downregulating the Wnt signaling and inducing forkhead box O3 (FoxO3) activation, respectively. Notably, the combined tumor-selective ROS generation and Zn²⁺-induced antioxidation dysfunction potently trigger intratumoral oxidative damage leading to both cellular apoptosis and ferroptosis. This nanomedicine, capable of synchronously treating CSCs and bulk tumor cells, has been demonstrated to effectively inhibit the growth, postoperative recurrence and metastasis of orthotopic triple-negative breast tumors <i>in vivo</i>, offering an encouraging candidate of cancer therapeutic agents for treating CSCs-enriched malignancy.