Eradication of cancer stem cells (CSC) enriched tumors remains a formidable challenge due to their intrinsic drug resistance and robust cholesterol-driven anti-ferroptotic defenses. Herein, we report a cholesterol oxidase (COD)-loaded hollow mesoporous zinc-copper sulfide (COD@HMZCS-HA) nanomedicine designed to eliminate CSC via self-fueling catalysis-driven membrane destabilization. After targeted tumor accumulation, the released components function synergistically to overcome therapeutic resistance. Specifically, COD-mediated cholesterol depletion acts as an indispensable sensitizing step by dismantling the biophysical membrane barrier of protective lipid rafts and inactivating the 7-dehydrocholesterol (7-DHC)-mediated endogenous “molecular brake” on LPO. Concurrently, a self-fueling catalytic cycle, involving Cu+-mediated •OH generation, Zn2+-induced •O2⁻ accumulation and H2S-triggered hypoxia relief and intracellular acidification, drove the massive amplification and propagation of lethal LPO storm. Through simultaneous sustainment of local oxygen availability and abrogation of cholesterol-dependent membrane defenses, COD@HMZCS-HA effectively bypasses classical resistance pathways, culminating in irreversible CSC ferroptosis. In vitro and in vivo studies demonstrate that the COD@HMZCS-HA shows potent antitumor and antimetastatic efficacy due to the extensive ablation of CSC coupled with the disruption of invasive lipid rafts. Collectively, the developed self-fueling catalysis strategy simultaneously overcomes the hypoxic TME barrier and disrupts cholesterol-dependent anti-ferroptotic defenses, offering a promising therapeutic paradigm for elimination of CSC-enriched tumors.
Huang et al. (Sun,) studied this question.