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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Cancer stem cells (CSCs) present a significant therapeutic challenge due to inherent drug resistance and cholesterol-dependent anti-ferroptotic mechanisms.
• Existing treatments struggle to overcome the protective barriers and resistance pathways employed by CSCs within the tumor microenvironment (TME).

Purpose of the Study:

• To develop and evaluate a novel nanomedicine, cholesterol oxidase (COD)-loaded hollow mesoporous zinc-copper sulfide (COD@HMZCS-HA), for targeted elimination of CSCs.
• To investigate the synergistic effects of cholesterol depletion and self-fueling catalysis in overcoming CSC resistance and inducing ferroptosis.

Main Methods:

• Design of COD@HMZCS-HA nanomedicine for targeted tumor accumulation and release of active components.
• Utilizing cholesterol oxidase (COD) to deplete cholesterol, dismantle lipid rafts, and inactivate the 7-dehydrocholesterol (7-DHC) brake on lipid peroxidation (LPO).
• Implementing a self-fueling catalytic cycle involving Cu+, Zn2+, and H2S to generate reactive oxygen species (ROS), relieve hypoxia, and induce intracellular acidification, amplifying LPO.

Main Results:

• COD@HMZCS-HA effectively depleted cholesterol, destabilized CSC membranes, and sensitized cells to ferroptosis.
• The self-fueling catalysis amplified LPO, leading to a ferroptotic storm and overcoming hypoxia within the TME.
• In vitro and in vivo studies demonstrated potent antitumor and antimetastatic efficacy through CSC ablation and disruption of lipid rafts.

Conclusions:

• The developed self-fueling catalysis strategy effectively overcomes TME hypoxia and cholesterol-dependent anti-ferroptotic defenses.
• COD@HMZCS-HA nanomedicine offers a promising therapeutic paradigm for the elimination of CSC-enriched tumors by inducing irreversible ferroptosis.
• This approach bypasses classical resistance pathways, highlighting its potential for improved cancer treatment outcomes.