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.