From Molecular Interactions to Nanocarrier Design: Coarse-Grained Modeling of PEG Self-Assembly and Hindsiilactone Encapsulation.

Polyethylene glycol (PEG)-based nanocarriers represent a promising strategy for delivering hydrophobic natural products like Hindsiilactone A (HINA), yet the molecular mechanisms governing polymer-drug interactions and optimal formulation parameters remain poorly understood. This study establishes quantitative design principles for PEG-based nanocarriers through a systematic molecular dynamics investigation of concentration-dependent assembly mechanisms. Martini 3 coarse-grained models were validated against all-atom simulations, achieving structural accuracy while enabling large-scale nanocarrier studies. Comprehensive analysis of PEG-HINA systems reveals distinct mechanistic regimes: optimal encapsulation efficiency (70-76%) occurs at low concentrations with compact particle sizes (8.4-9.8 nm). High HINA concentrations result in a compromised encapsulation efficiency (28.9-58.3%) and increased size heterogeneity (11.8-16.0 nm). The study identifies optimal PEG/HINA ratios (4:1-2:1), concentration windows for reproducible synthesis, and size-loading relationships for therapeutic targeting. This validated computational framework enables the systematic exploration of natural product nanocarriers, providing rational design strategies for sustainable drug delivery system development and clinical translation of bioactive compounds.