Next-generation stealth lipid-based nanocarriers: advances in PEGylation and emerging amide-containing polymer alternatives.

Surface chemistry affects the in vivo behavior of lipid-based nanocarriers, through lipid-PEGylation (polyethylene glycol, PEG), which forms a steric barrier at the nanoparticle interface and extends systemic circulation. This is relevant for clinically approved nanocarriers products, such as liposomes and lipid nanoparticles (LNPs), as many are PEGylated. However, drawbacks have emerged due to the widespread PEG use, including anti-PEG antibodies accelerated blood clearance (ABC) upon repeat dosing, and hypersensitivity reactions (HSRs) such as complement activation-related pseudoallergy (CARPA). Moreover, the steric barrier providing stealth properties hinders cargo delivery by reducing cell interactions and limiting endosomal escape. Numerous studies link lipid-PEG chemistry to these outcomes, although results vary across formulations and remain debated. Here, we review stealth strategies for lipid nanocarriers, focusing on liposomes and LNPs and compare PEG engineering with selected amide-based polymer alternatives. We summarize key PEGylation design levers: lipid-PEG anchor modification, end-group chemistry, chain length and branched architectures, and cleavable linkers aimed at preserving stealth while mitigating immune responses and intracellular delivery barriers. We then examine three amide-containing polymer families (polysarcosine, poly(2-oxazoline)s, and poly(N-vinylamide)s) selected for their PEG-like surface behavior. We relate biological outcomes and delivery efficiency to practical manufacturing factors, synthetic feasibility and the tunability of lipid-polymer conjugates.