Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability

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 poly-unsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been pur-ported 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 formu-lation 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 progres-sion in both ApoE-/-and Ldlr-/-experimental models. Plaque composition analysis demonstrates that lipo-somal 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.

Automated summary

Atherosclerosis is a chronic vascular disease characterized by plaque formation in artery walls, and docosahexaenoic acid (DHA) has been suggested as a therapeutic option due to its anti-inflammatory and antioxidant properties. However, inconsistent results in clinical trials may be due to variations in DHA formulation and bioavailability. In this study, an injectable liposomal DHA formulation was developed, which protected DHA against degradation and increased its concentration within plaques. This formulation showed promising results in attenuating atherosclerosis progression and stabilizing plaques in experimental models.