Targeting cancer stem-like cells via cholesterol modulation and ferroptosis induction using a multifunctional nanoplatform to overcome drug resistance.

Overcoming therapy resistance in triple-negative breast cancer (TNBC) requires the effective targeting of cancer stem-like cells (CSCs). TNBC is characterized by hyperactivation of the mevalonate pathway, leading to cholesterol accumulation in CSC membranes, which alters membrane properties, enhances stemness, and restricts both drug penetration and lipid peroxidation-a key driver of ferroptosis. Here, we develop Fe/CDP, a nanoparticle with a Fe3O4 core coated with chondroitin sulfate and loaded with pravastatin, a mevalonate pathway inhibitor, and doxorubicin (DOX). In TNBC mouse models, Fe/CDP selectively targets tumors and CSCs via CD44-chondroitin sulfate interactions, enabling localized drug release. Pravastatin suppresses cholesterol biosynthesis, restoring membrane rigidity and fluidity, thereby reducing CSC stemness, disrupting P-glycoprotein function, and downregulating ALDH1, which enhances DOX sensitivity via the EGFR/Src/HMGCR axis. Moreover, cholesterol depletion facilitates lipid peroxidation, synergizing with Fe3O4 to trigger ferroptosis through CoQ10/GPX4/FSP1 downregulation. By eliminating both bulk tumor cells and CSCs, Fe/CDP provides a cholesterol-modulating strategy to overcome TNBC drug resistance.