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<p>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 <i>via</i> 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<sup>+</sup>-mediated •OH generation, Zn<sup>2+</sup>-induced •O<sub>2</sub><sup>⁻</sup> accumulation and H<sub>2</sub>S-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.</p> Graphical Abstract <p></p>

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Self-fueling catalysis-driven membrane destabilization triggers CSC-enriched tumors ablation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月24日

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  • Lin Huang,
  • Basheng Hu,
  • Guochao Wu,
  • Wenjie Ma,
  • Jiaoyang Qiu,
  • Jiaoyang Zhu,
  • Jing Yang,
  • Haobin Cai,
  • Qingdeng Fan,
  • Bin Ren,
  • Chunmei Chen,
  • Zehui Wang,
  • Jie Feng,
  • Yitong Li,
  • Sugeun Yang,
  • Chenggong Yan,
  • Xiangrong Yu,
  • Zhigang Liu,
  • Zheyu Shen

摘要

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.

Graphical Abstract