Research squareJun 22, 2026

Reduced effectiveness from PEG in lipid nanoparticles continues despite formulation changes for mRNA delivery

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 23, 2026

Abstract

None of the formulation adjustments prevented efficacy loss associated with elevated anti-PEG immunoglobulin responses.

A single dose of lipid nanoparticles (LNPs) can trigger adaptive immune responses against polyethylene glycol (PEG), leading to neutralization of subsequent doses.
Adjustments in PEG-lipid chemistry, PEG concentration, mRNA cargo, and administration route did not mitigate efficacy loss after initial anti-PEG antibody responses.
Efficacy loss was consistently linked to increased levels of anti-PEG immunoglobulin M (IgM) and, in some cases, immunoglobulin G (IgG).
Lowering PEG concentration reduced immunogenicity but also decreased potency of the LNPs.
Intraperitoneal administration resulted in the strongest immune responses upon re-dosing with LNPs.
Anti-PEG immune responses compromised the delivery efficacy of any PEGylated LNP formulation, including an FDA-approved version.

Simplified

Lipid nanoparticles (LNPs) are clinically proven mRNA delivery vehicles, and repeated administration is often required to maintain therapeutic or prophylactic benefit. However, a single dose can provoke adaptive immune responses against polyethylene glycol (PEG), a polymeric excipient on the LNP surface. In this event, resultant anti-PEG antibodies neutralize subsequent LNP doses, causing efficacy loss and limiting therapeutic utility. Here, we investigated whether altering the LNP formulation between initial and subsequent doses could mitigate PEG-associated efficacy loss. Following the administration of an LNP known to elicit anti-PEG antibodies, we re-dosed with LNPs formulated with varied PEG-lipid chemistry, PEG concentration, mRNA cargo, and administration route. None of these adjustments prevented efficacy loss, which consistently correlated with elevated anti-PEG immunoglobulin M (IgM) and, in some cases, immunoglobulin G (IgG). Reduced PEG concentration diminished immunogenicity but also potency, and intraperitoneal dosing elicited the strongest responses upon repeat injection. Further, LNPs that elicit anti-PEG antibodies also impaired the subsequent delivery of an FDA-approved MC3 formulation, suggesting that anti-PEG immune responses can compromise any PEGylated LNP formulation. Together, these findings demonstrate that PEG-associated efficacy loss cannot be resolved through formulation optimization alone. Instead, they suggest that the ionizable lipid's engagement of innate immune receptors is the primary determinant of repeat dosing success.