Tumor-Derived Extracellular Vesicles Combining ALOX15 and RSL3 Enhance Lipid Oxidation and Antitumor Activity

Background/Objectives: Enhancing lipid peroxide formation while impairing antioxidant defenses represents a promising strategy for ferroptosis-based cancer therapy. This study aimed to evaluate a tumor-derived extracellular vesicle (EV) formulation combining ALOX15-associated lipid oxidation with RSL3-mediated inhibition of GPX4.

Methods

RSL3@ALOX15-MPs were prepared by associating the GPX4 inhibitor RSL3 with ALOX15-containing EVs derived from 4T1 tumor cells. The formulation was characterized, and its effects on lipid oxidation, cell viability, and ferroptosis-associated responses were evaluated in vitro. Antitumor efficacy, biodistribution, tumor immune-cell phenotypes, and preliminary tolerability were assessed in 4T1 tumor-bearing mice.