Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability

Suet Yen Chong, Xiaoyuan Wang, Louis van Bloois, Chenyuan Huang, Nilofer Sayed Syeda, Sitong Zhang, Hui Jun Ting, Vaarsha Nair, Yuanzhe Lin, Charles Kang Liang Lou, Ayca Altay Benetti, Xiaodong Yu, Nicole Jia Ying Lim, Michelle Siying Tan, Hwee Ying Lim, Sheau Yng Lim, Chung Hwee Thiam, Wen Donq Looi, Olga Zharkova, Nicholas W.S. ChewCheng Han Ng, Glenn Kunnath Bonney, Mark Muthiah, Xiaoyuan Chen, Giorgia Pastorin, A. Mark Richards, Veronique Angeli, Gert Storm*, Jiong Wei Wang

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake. To fully exploit its potential therapeutic effects, we have developed an injectable liposomal DHA formulation intended for intravenous administration as a plaque-targeted nanomedicine. The liposomal formulation protects DHA against chemical degradation and increases its local concentration within atherosclerotic lesions. Mechanistically, DHA liposomes are readily phagocytosed by activated macrophages, exert potent anti-inflammatory and antioxidant effects, and inhibit foam cell formation. Upon intravenous administration, DHA liposomes accumulate preferentially in atherosclerotic lesional macrophages and promote polarization of macrophages towards an anti-inflammatory M2 phenotype, resulting in attenuation of atherosclerosis progression in both ApoE−/− and Ldlr−/− experimental models. Plaque composition analysis demonstrates that liposomal DHA inhibits macrophage infiltration, reduces lipid deposition, and increases collagen content, thus improving the stability of atherosclerotic plaques against rupture. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) further reveals that DHA liposomes can partly restore the complex lipid profile of the plaques to that of early-stage plaques. In conclusion, DHA liposomes offer a promising approach for applying DHA to stabilize atherosclerotic plaques and attenuate atherosclerosis progression, thereby preventing atherosclerosis-related cardiovascular events.

Original languageEnglish
Pages (from-to)344-364
Number of pages21
JournalJournal of Controlled Release
Early online date7 Jul 2023
Publication statusPublished - Aug 2023


  • Atherosclerosis
  • Cardiovascular disease
  • DHA
  • Inflammation
  • Liposomes
  • M2 macrophages
  • Omega-3 polyunsaturated fatty acid
  • Plaque vulnerability


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