Nanoemulsion-Enhanced Cardiac Delivery of Omega-3 Fatty Acids Reduces Myocardial Fibrosis and Improves Diastolic Function in a Murine HFpEF Model

Omega-3 polyunsaturated fatty acids (PUFAs) exert cardiometabolic and anti-inflammatory effects, yet their clinical efficacy remains inconsistent, potentially due to limited tissue bioavailability. In this work, we evaluated whether a self-emulsifying nanoformulation of omega-3 fatty acids (NG omega-3) enhances cardiac uptake and improves functional outcomes in a murine model of heart failure with preserved ejection fraction (HFpEF). First, C57BL/6J mice received conventional omega-3 oil or NG omega-3 by oral gavage for 10 days, and fatty-acid distribution was subsequently quantified by gas chromatography. While the administration of both omega-3 formulations achieved comparable plasma EPA and DHA levels, NG omega-3 significantly increased myocardial omega-3 fatty-acid accumulation, particularly EPA. Subsequently, HFpEF was induced in mice by administration of a high-fat diet combined with Nw-nitro-L-arginine methyl ester (L-NAME). After 10 weeks of treatment, cardiac function was assessed by echocardiography and strain analysis, and myocardial fibrosis and immunecell infiltration were evaluated histologically. NG omega-3 administration was associated with reduced left-ventricular wall thickening, improved diastolic indices, and enhanced global longitudinal strain compared with conventional omega-3. NG omega-3 also markedly attenuated myocardial collagen deposition, indicating reduced fibrosis, while both formulations similarly decreased CD4⁺ immune-cell infiltration. These findings demonstrate that nanoemulsion-based delivery enhances myocardial bioavailability of omega-3 fatty acids and improves structural remodeling and diastolic function in HFpEF, suggesting that tissue delivery, rather than circulating levels alone, is a key determinant of omega-3 therapeutic efficacy.