Nanomedicine (London, England)Jul 23, 2026

New stealth fat-based carriers: improvements in PEG coating and new amide polymer options

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 24, 2026

Abstract

Surface chemistry influences the behavior of lipid-based nanocarriers, particularly through PEGylation.

PEGylation creates a steric barrier that enhances the circulation time of lipid nanoparticles in the body.
The use of PEG can lead to the development of anti-PEG antibodies, resulting in accelerated blood clearance upon repeat dosing.
Hypersensitivity reactions, such as complement activation-related pseudoallergy, have been associated with PEGylated nanocarriers.
While PEGylation offers stealth properties, it can also limit the effectiveness of cargo delivery by reducing interactions with cells.
Alternative amide-based polymers may exhibit similar stealth characteristics while potentially reducing immune responses and improving delivery efficiency.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

M.B., G.P., and A.D. are named as inventors on a patent concerning PNMVA polymer for lipid nanoparticle surface modification (WO2024/227713 A1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

PubMed

New stealth fat-based carriers: improvements in PEG coating and new amide polymer options

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the mrna technology brief

Abstract

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the mrna technology brief