Unraveling the role of PEGylation in the anti-aggregation stability of lipid nanoparticles

PEGylation is a key strategy to increase the storage stability and prolong the <i>in vivo</i> circulation time of lipid-based drug delivery systems by enhancing the anti-aggregation stability of nanocarriers, yet the relevant molecular mechanism remains unrevealed. This study employs multiscale approaches integrating molecular dynamics (MD) simulations and experimental characterization to comprehensively elucidate the quantitative structure-activity relationship (QSAR) between colloidal stability and molecular properties (<i>i.e.</i>, molecular weight, surface grafting density, and molecular polarity) and environmental temperature of PEG. The results show that while electrostatic repulsion enhances the short-range repulsion, the dominant contribution to the anti-aggregation performance arises from the steric hindrance associated with PEG chain compression. The compression interfacial energy of the PEG layer follows the classical polymer brush theory, with the elastic modulus proportional to the grafting density and inversely proportional to the chain length. Moreover, increasing PEG polarity leads to brush layer thickening and reduced stiffness <i>via</i> enhanced hydration, while lowering the temperature decreases brush stiffness but increases equilibrium distance. Energy decomposition analysis reveals that the repulsive interaction between PEG layers is primarily driven by conformational entropy loss. These results are further validated by long-term stability tests of PEGylated liposomes fabricated <i>via</i> microfluidics. This work offers critical molecular insights and practical guidance for the rational design of PEGylated nanoparticles with optimal stability.