Strategies to prevent water soluble drug leakage from nanovesicles in blood circulation: A coarse-grained molecular study

[Display omitted] •Two strategies to prevent drug leakage were studied by coarse-grained molecular simulation.•CHolSH can fill the holes in the hydrophobic layer to avoid drug leakage.•AuNP shows “physically cross-link” with hydrophobic layer to inhibit drug leakage.•Janus AuNP possesses higher dispersibility than randomly modified AuNP. Nanovesicle has been extensively investigated and widely used in biomedical applications. However, the premature leakage of water-soluble drugs from nanovesicle seriously limits the further clinical use. It’s of great significance to develop effective strategy for leakage inhibition. Herein, we explored effective strategies to prevent drug leakage through coarse-grained molecular simulations. We investigated the influences of doping of cholesteryl hemisuccinate and gold nanoparticles on the morphology and structure of nanovesicle. We found that cholesteryl hemisuccinate can effectively improve the hole defects in the hydrophobic layer to adjust the drug diffusion performance. Then, we studied the effects of particle size, concentration, and surface chemical properties of gold nanoparticles on the drug leakage of nanovesicle. We further verified that the “physical cross-linking” of gold nanoparticles led to more drugs leaking from the nanovesicle cavity. With surface modification, the side effects of “physical cross-linking” were improved with the enhanced dispersion of gold nanoparticles.