Ginsenoside Rg3-containing ionizable lipid nanoparticles for siRNA delivery

Lipid nanoparticles (LNPs) are promising carriers for nucleic acid delivery. However, cholesterol (Chol), a common component of LNPs, may cause adverse effects such as allergic reactions and hyperlipidemia upon excessive uptake and has been implicated in promoting tumor progression. In this study, we developed ginsenoside Rg3-based nanoparticles (Rg3-LNPs) as a safer and more effective alternative to Chol-containing LNPs (Chol-LNPs). An optimal Chol-free LNP formulation containing 40 mol% Rg3 was developed via orthogonal experimental design. The Rg3-LNPs exhibited enhanced cellular uptake, showing 1.47-fold higher efficiency than Chol-LNPs, and improved cell viability (1.17-fold higher at a total lipid concentration of 50 µg mL⁻¹). When loaded with STAT3-targeting siRNA, Rg3-LNPs achieved superior gene silencing and cytotoxicity in 4T1 invasive breast cancer cells. These results demonstrate that ginsenoside Rg3 can effectively replace Chol in LNPs, providing an innovative and safe delivery vector for siRNA-based cancer therapy.