Circular RNA lipid nanoparticle vaccine against SARS-CoV-2

🥈 Top 2% JournalSep 15, 2025Proceedings of the National Academy of Sciences of the United States of America

Circular RNA vaccine delivered by fat nanoparticles against COVID-19

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Abstract

A 3.8-fold increase in antigen-specific reciprocal endpoint IgG titers was observed with circRNA LNPs compared to mRNA LNPs.

Protein-coding circular RNA (circRNA) shows increased stability and potentially reduced immunogenicity compared to traditional mRNA.
An optimized lipid nanoparticle (LNP) platform was developed for effective delivery of circRNA to immune cells.
Substantial accumulation of circRNA LNPs in draining lymph nodes and strong dendritic cell maturation were observed shortly after intramuscular administration in mice.
Robust antibody production and enhanced immune responses were demonstrated with circRNA vaccination against SARS-CoV-2.
CircRNA LNPs elicited strong T1-biased cellular responses, indicating a different immune profile compared to mRNA LNPs.

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With the advent and widespread use of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), RNA vaccines have emerged as an exciting class of vaccine offering low cost, rapid development, and high modularity and manufacturability. Protein-coding circular RNA (circRNA) is an emerging class of RNA cargo that offers increased stability compared to mRNA with potentially reduced immunogenicity, but delivery technologies for intracellular delivery of circRNA remain underexplored. Here, we develop an optimized lipid nanoparticle (LNP) platform for circRNA delivery to immune cells, observing strong and durable transgene expression in vitro and in vivo. We employ a design-of-experiments (DoE) methodology to identify key formulation parameters for enhanced circRNA delivery and, upon intramuscular administration of our optimized circRNA LNPs to mice, observe substantial accumulation within draining lymph nodes and strong dendritic cell (DC) maturation at short time points. Applying this optimized circRNA LNP platform to vaccination against SARS-CoV-2, we demonstrate robust antibody production and enhanced immune responses in mice compared to vaccination with mRNA LNPs, including strong T1-biased cellular responses and a 3.8-fold increase in antigen-specific reciprocal endpoint IgG titers. These results provide insights into design criteria for circRNA LNP formulations and support the use of circRNA LNPs for vaccination against infectious diseases. h

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