Chemical and Biological Determinants of PEG-Lipid Shedding From Therapeutic Nanoparticles.

Polyethylene glycol (PEG)-lipids are widely used to engineer the interfacial properties of lipid-based nanomaterials, where they play a central role in governing colloidal stability and biological interactions. By forming a steric barrier at the nanoparticle surface, PEG-lipids reduce protein adsorption and extend circulation times. Additionally, PEG-lipids are increasingly functionalized with targeting moieties, representing a primary strategy to enable selective delivery. However, accumulating evidence indicates that PEG-lipids are not static components but instead undergo dynamic dissociation, or "shedding," upon exposure to biological environments. This interfacial exchange process alters nanoparticle behavior, promoting protein adsorption and accelerating clearance, while also enabling cellular interactions that facilitate uptake. Here, we present a conceptual framework for understanding PEG-lipid shedding as a coupled thermodynamic and kinetic process influenced by lipid chemical structure, nanocarrier membrane properties, and interactions with biomolecules. By synthesizing recent findings across experimental systems, we identify key factors that link PEG-lipid composition and nanoparticle architecture to desorption kinetics and biological outcomes. These insights provide guidance for the design of PEGylated nanomaterials with improved control over interfacial stability, immune recognition, and functional performance.