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Life sciences · Journal article
Pharmaceutics · October 23, 2026
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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. Results: The formulation exhibited EV-associated characteristics and an RSL3 loading content of approximately 3.8% relative to MP protein mass. In 4T1 cells, RSL3@ALOX15-MPs increased BODIPY-C11 oxidation to approximately five times the PBS control level and reduced cell viability to approximately 30%, compared with approximately 60% following RSL3-MP treatment. Ferrostatin-1, liproxstatin-1, and deferoxamine partially rescued cell viability and attenuated lipid oxidation. RSL3-containing formulations reduced total glutathione peroxidase activity, while ALOX15 inhibition attenuated lipid oxidation and cytotoxicity. The combined formulation also resulted in lower cell viability than a physical mixture of the individual formulations. In vivo, RSL3@ALOX15-MPs increased tumor RSL3 accumulation, altered intratumoral immune-cell phenotypes and cytokine levels, inhibited tumor growth, and prolonged survival. Conclusions: Combining ALOX15-associated lipid oxidation with RSL3 delivery using tumor-derived EVs enhanced ferroptosis-associated cytotoxicity in vitro and demonstrated antitumor efficacy in the 4T1 tumor model. Further studies are required to establish GPX4-specific effects and the causal contributions of ferroptosis and immune responses to the in vivo therapeutic outcomes.