HDL and LDL-bioinspired nanocarriers in acellular targeted delivery of Icariin for cardiac repair post myocardial infarction.

Myocardial infarction (MI) is a major ischemic heart condition that leads to the loss of billions of cardiomyocytes, triggering adverse ventricular remodeling and fibrotic tissue formation, which can ultimately result in heart failure. Current treatments fail to address cardiomyocyte loss, prompting interest in cardiac regeneration strategies. Although cell-based therapies have gained attention, they face limitations such as poor cell survival and engraftment. Acellular nanoformulations represent a promising alternative. In this study, protein-free bioinspired lipid nanoparticles mimicking low- and high-density lipoprotein; LDL and HDL-namely LDE and HDA-were developed and loaded with the phytomedicine Icariin. Both systems demonstrated high encapsulation efficiency (>90 %), favorable drug release profiles, and good serum stability. In vitro, LDE and HDA exhibited superior cellular uptake in H9c2 cells and significantly improved cell viability in doxorubicin-treated cultures compared to free Icariin. Pretreatment with LDE-Icariin effectively reduced cardiomyocyte apoptosis following doxorubicin exposure. Biodistribution analysis revealed enhanced targeting of infarcted myocardium by HDA over LDE in a rat MI model. Moreover, HDA markedly reduced cardiac damage and promoted regeneration more effectively than LDE. These findings highlight HDA and LDE as cost-effective, bioinspired nanoformulations for cardiac repair, with HDA showing superior targeting and therapeutic performance.