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

Our plain-English summary of Bio-inspired self-assembly of omega-3 fatty acids and peptides for responsive drug delivery, by S. Braccia, L. Alfano, M.C. Ragosta, et al (International Journal of Pharmaceutics: X, 2026).

The study

• Authors: S. Braccia, L. Alfano, M.C. Ragosta, R. Bellavita, G. D'Auria, E. Esposito, F. Donadio, S. Palladino, A. di Vaio, R. Camerlingo, L. Falcigno, A. Falanga, M. de Laurentiis, A. Giordano, S. Galdiero
• Journal: International Journal of Pharmaceutics: X
• Published: 2026;11:100558
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2026 The Authors.

In plain English

This was a laboratory study, with no patients, describing the development of nanoparticles built from the omega-3 fatty acid eicosapentaenoic acid (EPA) carrying peptides on their surface. The authors conjugated EPA to the cell-penetrating peptide gH625, to a targeting peptide (falGea) and to doxorubicin (Dox) or pemetrexed (PEM) through a sequence cleavable by matrix metalloproteinase-9 (MMP-9). Nanoparticles were characterised by light scattering, electron microscopy, circular dichroism and NMR, and tested on HeLa cervical cancer cells, HaCaT keratinocytes, MSTO-211H biphasic mesothelioma cells and non-tumoral MET-5 A mesothelial cells. Drug loading was 13.42% for doxorubicin and 8.83% for pemetrexed. With MMP-9, roughly 50% of Dox was released by 60 minutes and about 80% by 120 minutes, while the non-cleavable control released little. In HeLa cells at 6 micromolar Dox and 72 hours, EPA-gH-Dox left about 40% viability versus about 10% for free Dox. In MSTO-211H cells, EPA-gH-TP-PEM reduced viability to about 50-60% at 50 nanomolar PEM at 72 hours. Five authors declared a patent on EPA-based nanoparticles.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro laboratory study: synthesis and physicochemical characterisation of EPA-based nanoparticles plus cell-culture testing
• Who was studied: Human cell lines only: HeLa cervical cancer cells, HaCaT keratinocytes, MSTO-211H biphasic mesothelioma cells and MET-5 A non-tumoral mesothelial cells (no animals or patients)
• Exposure: EPA-based nanoparticles decorated with the cell-penetrating peptide gH625, the targeting peptide falGea, and doxorubicin or pemetrexed linked through the MMP-9 cleavable sequence PLGSYL; free Dox and free PEM used for comparison
• Main results:
  • Drug loading capacity was 13.42% for doxorubicin and 8.83% for pemetrexed
  • Enzyme-triggered release: about 50% of Dox released from EPA-gH-Dox at 60 min and about 80% at 120 min with MMP-9; no significant release from the non-cleavable control EPA-gH-Dox-NC
  • Flow cytometry in HeLa cells: about 71% Dox-positive cells with EPA-gH-Dox versus about 2.5% with the non-cleavable control
  • HeLa viability at a Dox concentration of 6 micromolar and 72 hours: about 40% with EPA-gH-Dox, about 10% with free Dox
  • In HaCaT keratinocytes, free Dox was toxic from 48 hours while EPA-gH-Dox did not reduce viability; minimal toxicity only at 300 micromolar EPA-gH-Dox at 72 hours
  • In non-tumoral MET-5 A mesothelial cells, EPA and EPA-gH-TP showed no detectable cytotoxicity up to 100 micromolar at 48 and 72 hours
  • In MSTO-211H mesothelioma cells, the carrier EPA-gH-TP alone lowered viability by 40% at 72 hours
  • In MSTO-211H mesothelioma cells at 72 hours, EPA-gH-TP-PEM reduced viability to about 50-60% at a PEM concentration of 50 nanomolar, comparable to free pemetrexed
  • Nanoparticle size: EPA-gH-Dox about 197 nm (PdI 0.12), EPA-gH-TP-PEM 228 nm (PdI 0.16); zeta potentials slightly positive
  • Western blotting showed EGFR and MMP-9 overexpressed in MSTO-211H compared with MET-5 A
• The authors' conclusion: The authors concluded that they had produced the first nanocarrier made entirely of EPA, that it showed in vitro biocompatibility with healthy cells, MMP-9-triggered drug release and anticancer activity, and that it could serve as a drug delivery platform, including in mesothelioma models
• Limitations the authors state:
  • The authors stated that the 2D cell-culture work is preliminary and does not reproduce the tumour microenvironment, with 3D and in vivo studies still needed
  • The authors stated the formulation suits only short-term studies and must be optimised for prolonged circulation, as serum stability declined by 72 hours
  • The authors noted that in vivo biodistribution, clearance and safety remain to be evaluated

Topics

Medical terms in this study, explained in our Lexicon: Quality of Life, Doxorubicin, Pemetrexed (Alimta), Mesothelioma.

Related studies

• A Deep Look Into Erionite Fibres: an Electron Microscopy Investigation of their Self-Assembly — R. Matassa, G. Familiari, et al. (2015)
• Biological autoxidation. II. Cholesterol esters as inert barrier antioxidants. Self-assembly of porous membrane sacs. An hypothesis — S.H. Kon (1978)
• Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles — A.H. Colby, R. Liu, et al. (2016)
• Lipolysis of polyenoic fatty acid esters of human chylomicrons by lipoprotein lipase — B. Ekström, A. Nilsson, et al. (1989)
• Iron translocation by free fatty acids — M.W. Qian, J.W. Eaton (1991)
• Free fatty acids inhibit protein tyrosine phosphatase 1B and activate Akt — E. Shibata, T. Kanno, et al. (2013)

Browse return to medical research.