Bromelain-functionalized omega-3 nanocarriers for targeted icariin delivery: a multifunctional shield for cardiac repair in doxorubicin-induced injury

The major loss of cardiomyocytes caused by several cardiovascular diseases as myocardial infarction, increases the incidence of heart failure. Thus, there is an urgent need to develop novel therapies that can enhance angiogenesis and decrease the rate of cardiac cell apoptosis. The use of nanoparticles that can passively target infarcted myocardium can be appealing. Icariin is a natural product with various cardioprotective properties that can be encapsulated within nanostructured lipid carriers (NLCs) to enhance its therapeutic effect. Incorporating bioactive excipients such as omega-3 oils and bromelain into the NLC formulation can potentiate its cardioreparative effects. Therefore, the use of such nanoformulation can be an attractive option to minimize cardiac damage. Optimized bromelain-coated and uncoated NLCs loaded with icariin were successfully developed, demonstrating efficient bromelain surface modification, high drug entrapment, and a favorable release profile. In vitro experiments using doxorubicin (DOX)-treated H9c2 cardiomyocytes highlighted the superior cellular uptake of NLCs compared to the free solution. Notably, pretreatment with optimized bromelain-coated and uncoated icariin-loaded NLCs significantly improved cell viability and reduced apoptotic rates, indicating their potential role in cardioprotection. The therapeutic effect of NLCs was markedly enhanced relative to free icariin, demonstrating the added value of nano-formulation. Combination index (CI) analysis using Compusyn further verified the synergistic interaction between nano-formulated icariin and bioactive excipients, enabling improved therapeutic outcomes with lower effective doses. These findings highlight the potential of NLC-based delivery systems in counteracting doxorubicin-induced cardiotoxicity, supporting further preclinical studies for clinical translation.