Key Takeaways & Executive Findings
- •• • C18-POx-LNPs achieved over 200-fold higher transfection efficiency than PEG-LNPs in mice with pre-existing anti-PEG antibodies, directly addressing the clinical bottleneck of reduced efficacy in PEG-sensitized populations. • • Single-tailed C18-POx conjugates produced LNPs with smaller particle sizes and superior freeze-thaw stability compared to other POx variants, indicating enhanced colloidal stability for storage and handling. • • C18-POx-LNPs fully replacing DMG-PEG maintained comparable in vivo transfection efficiency to PEG-LNPs in naive mice, demonstrating non-inferior performance without PEG. • • Repeated POx-LNP administration elicited dose-dependent anti-POx IgM and IgG responses, with antibody titers inversely correlated with POx hydrophilicity (PEtOx > PMeOx), highlighting the need to balance stealth and immunogenicity.
Abstract
Messenger RNA-lipid nanoparticle (mRNA-LNP) vaccines have demonstrated extraordinary efficacy against severe acute respiratory syndrome coronavirus 2, establishing LNPs as the premier platform for mRNA therapeutics. However, the pervasive presence of anti-polyethylene glycol (PEG) antibodies undermines PEGylated LNP performance by diminishing therapeutic efficacy. To address this challenge, we synthesized a panel of lipid-poly(2-oxazoline) (lipid-POx) conjugates as alternatives to lipid-PEG and systematically evaluated how their polymer backbone, degree of polymerization, and lipid tail structure influence LNP physicochemical properties and mRNA delivery performance. Among POx-LNPs formulated with heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate (SM-102) as the base lipid, those constructed with single-tailed C18-POx exhibited smaller particle sizes and superior freeze-thaw stability. These C18-POx-LNPs maintained comparable in vivo transfection efficiency to PEG-LNPs even when fully replacing 1,2-dimyristoyl-sn-glycero-3 (DMG)-PEG. Notably, in mice bearing pre-existing anti-PEG antibodies, C18-POx-LNPs demonstrated over 200-fold higher transfection efficiency than PEG-LNPs. Additionally, repeated administration of POx-LNPs induced dose-dependent anti-POx immunoglobulin M (IgM) and IgG responses, with antibody titers inversely correlated with POx hydrophilicity. This study underscores the effectiveness of substituting PEG with POx in LNP construction to address the transfection efficiency in populations with pre-existing anti-PEG antibodies, and would inspire the development of more hydrophilic polymers for LNP formulation.
1. Introduction
The clinical success of mRNA-LNP vaccines against SARS-CoV-2, with over one billion doses administered, has cemented LNPs as the leading platform for mRNA therapeutics. However, the ubiquitous use of PEG in consumer products and pharmaceuticals has driven a rise in pre-existing anti-PEG antibodies from 0.2% in 1984 to over 70% by 2022. These antibodies accelerate clearance of PEGylated LNPs, reduce transfection efficiency, and can trigger complement-mediated hypersensitivity reactions, including rare anaphylaxis during COVID-19 vaccination. This immunogenic barrier represents a critical bottleneck for repeated dosing and for populations with pre-existing immunity, necessitating alternative stealth polymers that retain PEG's stabilizing benefits without its immunogenicity.
This study systematically evaluates lipid-poly(2-oxazoline) (lipid-POx) conjugates as PEG replacements in LNPs. By varying polymer backbone, degree of polymerization, and lipid tail structure, the authors identify C18-POx formulations that achieve over 200-fold higher transfection efficiency than PEG-LNPs in anti-PEG antibody-bearing mice, while maintaining comparable efficacy in naive animals. These findings offer a concrete path to circumvent anti-PEG immunity, with implications for next-generation mRNA vaccines and therapeutics.
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LI Minhui, MA Sheng, SHEN Mengjie, WAN Renming, LONG Jiang'ai, JIANG Yuhang, LIANG Hanzhi, GUO Zhaopei, MA Xinpeng, SONG Wantong (2026). Poly(2-oxazoline) Decorated Lipid Nanoparticles for Robust mRNA Delivery in the Presence of Pre-existing Anti-PEG Antibodies. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3634-0
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Frequently Asked Questions
What is the mechanism by which C18-POx-LNPs evade anti-PEG antibodies and achieve over 200-fold higher transfection efficiency in pre-sensitized mice?
The evasion is attributed to the absence of PEG epitopes on the LNP surface, preventing recognition by anti-PEG antibodies. The POx polymer, particularly PMeOx, provides stealth properties without cross-reactivity, allowing LNPs to avoid accelerated clearance and maintain transfection activity. The study shows that C18-PMeOx 23-LNPs retained full transfection efficacy in PEG-sensitized mice, whereas PEG-LNPs lost nearly all activity.
How does the degree of polymerization and lipid tail structure of lipid-POx conjugates affect LNP particle size and stability?
Single-tailed C18-POx conjugates produced LNPs with smaller particle sizes and superior freeze-thaw stability compared to other POx variants. This suggests that the lipid tail structure influences the packing and stability of the LNP, while the polymer length modulates surface properties. The optimal formulation likely balances steric stabilization and particle integrity.
What are the immunogenicity profiles of POx-LNPs upon repeated administration, and how do they compare to PEG-LNPs?
Repeated POx-LNP administration induced dose-dependent anti-POx IgM and IgG responses, with PEtOx provoking higher titers than PMeOx. Anti-POx IgG persisted for over 50 days. While POx is generally considered lower immunogenicity, this study shows that under a vaccine-like schedule (two doses 21 days apart), POx can elicit antibodies. However, the titers were inversely correlated with hydrophilicity, suggesting that more hydrophilic POx variants like PMeOx may be less immunogenic.
What are the scalability and manufacturing compatibility of lipid-POx conjugates for clinical translation?
The synthesis of lipid-POx via living cationic ring-opening polymerization is precise, tunable, and scalable via GMP-compatible processes. These conjugates are fully compatible with microfluidic-based LNP manufacturing platforms used in commercial mRNA vaccine production, enabling seamless integration into existing industrial pipelines.
How does the biodistribution of POx-LNPs differ from PEG-LNPs, and what implications does this have for tissue-specific delivery?
POx-LNPs exhibit differential biodistribution depending on the polymer type: PMeOx-LNPs favor trafficking into highly permeable immune tissues, while PEtOx-LNPs may promote hepatic uptake due to altered protein corona profiles. This suggests that POx chemistry can be tuned to direct LNPs to specific organs, potentially enhancing delivery to target tissues.
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