A novel algae oil-based emulsion enhances chemotherapy outcome in human cancer models

Cancer therapy remains challenged by limited treatment efficacy, cancer-related malnutrition and substantial toxicity, underscoring the need for novel strategies to improve therapeutic responses. Omega-3 fatty acids, particularly docosahexaenoic acid (DHA), exhibit both nutritional and bioactive properties, including anti-inflammatory effects and the ability to enhance tumor cell susceptibility to oxidative stress and ferroptosis. To improve stability and delivery, omega-3 fatty acids can be formulated into nanoemulsions that facilitate cellular uptake and may potentiate anticancer therapies. Therefore, we developed a panel of nanoemulsions with defined omega-3 and 9 fatty acid profiles derived from algae, fish and olive oils. All formulations exhibited high physicochemical stability, nanoscale droplet sizes and compendial quality. While pure oil showed minimal biological activity, nanoemulsification markedly increased cytotoxicity, and the novel DHA-rich algae oil emulsion displayed strong and selective antitumor effects without affecting normal fibroblasts. Combination studies indicated tumor type-dependent enhancement of chemotherapeutic efficacy. RNA sequencing indicated activation of ferroptosis-associated pathways and suppression of DNA replication and cell-cycle progression by the novel DHA-rich algae oil emulsion. To expand translational relevance for tumor specific target therapies, a HER2⁺/ER⁻ patient-derived breast cancer cell line and matched cancer-associated fibroblasts were established and characterized. In conclusion, these findings identify the new formulation prototype as a selective and biologically active nanocarrier for DHA which is capable of enhancing tumor type specific therapies, selective chemotherapeutic efficacy and potentially inducing ferroptosis-driven antiproliferative programs. These results highlight the promising potential of DHA as lipid component in a nanoscale droplet size formulation for future combination cancer therapies.