Bio-inspired self-assembly of omega-3 fatty acids and peptides for responsive drug delivery.

Cancer treatments often yield unsatisfactory long-term clinical outcomes due to issues such as drug resistance, systemic toxicity, and suboptimal efficacy. Therefore, there is a need to develop novel drug delivery platforms for personalized medicine to enhance patient quality of life. In this study, an eicosapentaenoic acid (EPA)-based delivery system was developed and characterized. The system was functionalized with two different anticancer drugs, doxorubicin or pemetrexed, using an on-demand release strategy based on a proteolytic sequence specifically recognized by metalloproteinase-9 (MMP-9), an enzyme overexpressed in various cancers. We set-up the formulation procedure to obtain EPA-based nanoparticles (EPA-NPs) with a diameter of approximately 200 nm and low polydispersity, which were characterized for their aggregation properties and structural stability. The therapeutic efficacy was initially analyzed on HeLa cells as a cancer model due to their high transfection efficiency, reproducibility, and overexpression of MMP-9, using doxorubicin (Dox) as the drug. Enzyme-triggered drug release studies showed a rapid and controlled release profile, with approximately 80% of Dox released within 120 min in the presence of MMP-9. The efficient internalization was assessed using confocal microscopy; furthermore, Dox release induced an antiproliferative effect on HeLa cells (up to ∼60% cytotoxicity at 72 h) comparable to Dox free, while exhibiting no cytotoxicity toward healthy keratinocyte cells. Based on these results, the platform was later tested on a more disease-specific model, the mesothelioma, to confirm its relevance and adaptability for treating this aggressive cancer. These findings suggest that EPA nanoparticles could serve as a promising drug delivery platform.