Abstract
ABSTRACT
Lipid nanoparticles (LNPs) have rapidly emerged as the leading delivery platform for nucleic acid therapeutics due to their high encapsulation efficiency, scalable manufacturing, and clinical success in siRNA and mRNA medicines. Poly(ethylene glycol)‐lipids ((PEG)–lipids) have been central to this progress by providing steric stabilization, size control, and tunable biodistribution. However, PEGylation also introduces important limitations, including complement activation, pre‐existing and treatment‐induced anti‐PEG antibodies, and accelerated blood clearance, which increasingly constrain repeated and long‐term dosing strategies. This review focuses on recent advances in PEG‐alternative LNP designs, including non‐PEG polymers, zwitterionic and biomimetic lipids, polypeptides, and structurally modified PEG analogues. We compare how polymer chemistry, anchor geometry, and grafting architecture influence LNP formation, physicochemical properties, biodistribution, cellular uptake, and immunological outcomes. Moreover, we discuss key challenges that remain in translating PEG‐free and PEG‐modified LNPs toward clinical application and propose future directions to better understand in vivo behavior and enable rational design of next‐generation stealth LNPs. Overall, PEG lipid alternatives should not be viewed as simple PEG mimics, but as distinct surface‐engineering materials that create new nano‐bio interfaces and reshape LNP behavior in biological systems.