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. Myocardial incorporation of omega-3 fatty acids may be essential for reversing structural damage in heart failure. This study evaluated whether nanoemulsion-based delivery enhances cardiac uptake of omega-3 fatty acids and improves functional outcomes in a murine model of heart failure with preserved ejection fraction. A self-emulsifying nanoformulation of omega-3 fatty acids (NG Omega-3) was prepared and characterized. Mice received conventional omega-3 oil or NG-Omega-3 via oral gavage. Tissue fatty acid distribution was quantified using gas chromatography. Heart failure with preserved ejection fraction (HFpEF) was induced in C57BL/6J mice using a high-fat diet combined with nitro-L-arginine methyl ester (L-NAME) administration. After 10 weeks of treatment, cardiac function was assessed by echocardiography and strain analysis, and myocardial fibrosis and immune-cell infiltration were evaluated histologically. Results: Both formulations resulted in comparable plasma EPA and DHA plasma levels; however, NG-Omega-3 significantly increased myocardial accumulation of omega-3 fatty acids, particularly EPA, reduced left ventricular wall thickening, improved diastolic indexes, and enhanced global longitudinal strain compared with conventional omega-3. NG-Omega-3 markedly attenuated myocardial collagen deposition, indicating reduced fibrosis. Both omega-3 formulations decreased CD4⁺ immune-cell infiltration in cardiac tissue. Nanoemulsion delivery enhances myocardial bioavailability of omega-3 fatty acids and is associated with improved structural remodeling and diastolic function in HFpEF mice. These findings suggest that improved cardiac muscle delivery of omega-3 fatty acids by nano-formulation, rather than circulating levels, determine omega-3 efficacy and may inform future nutritional strategies for cardiometabolic disease.