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# A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation - PubMed

**URL:** https://pubmed.ncbi.nlm.nih.gov/37403357/

**Saved:** 2025-12-11T22:27:49.691Z

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Mol Ther
. 2023 Aug 2;31(8):2360-2375. doi: 10.1016/j.ymthe.2023.06.017. Epub 2023 Jul 3.
A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation
Taishi Kimura 1, Joseph M Leal 2, Adrian Simpson 2, Nikole L Warner 2, Bryan J Berube 2, Jacob F Archer 2, Stephanie Park 2, Ryan Kurtz 2, Troy Hinkley 2, Katrina Nicholes 2, Shibbu Sharma 2, Malcolm S Duthie 2, Peter Berglund 2, Steven G Reed 2, Amit P Khandhar 2, Jesse H Erasmus 3
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PMID: 37403357 PMCID: PMC10422015 DOI: 10.1016/j.ymthe.2023.06.017
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Abstract

RNA vaccines possess significant clinical promise in counteracting human diseases caused by infectious or cancerous threats. Self-amplifying replicon RNA (repRNA) has been thought to offer the potential for enhanced potency and dose sparing. However, repRNA is a potent trigger of innate immune responses in vivo, which can cause reduced transgene expression and dose-limiting reactogenicity, as highlighted by recent clinical trials. Here, we report that multivalent repRNA vaccination, necessitating higher doses of total RNA, could be safely achieved in mice by delivering multiple repRNAs with a localizing cationic nanocarrier formulation (LION). Intramuscular delivery of multivalent repRNA by LION resulted in localized biodistribution accompanied by significantly upregulated local innate immune responses and the induction of antigen-specific adaptive immune responses in the absence of systemic inflammatory responses. In contrast, repRNA delivered by lipid nanoparticles (LNPs) showed generalized biodistribution, a systemic inflammatory state, an increased body weight loss, and failed to induce neutralizing antibody responses in a multivalent composition. These findings suggest that in vivo delivery of repRNA by LION is a platform technology for safe and effective multivalent vaccination through mechanisms distinct from LNP-formulated repRNA vaccines.

Keywords: LION formulation; RNA vaccines; infectious diseases; innate immunity; lipid nanoparticles; multivalent vaccines; nanoparticle emulsion; reactogenicity; replicating RNA; side-effect.

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Conflict of interest statement

Declaration of interests T.K., J.M.L., A.S., N.L.W., S.P., R.K., J.F.A., B.J.B., T.H., K.N., S.S., A.K., M.S.D., P.B., S.G.R., and J.H.E. have equity interest in HDT Bio. J.H.E. is a consultant for InBios. P.B. is a consultant for Karkinox, and Chimeron. P.B. and J.H.E. are co-inventors on US patent application no. 63/011,860 “Nucleic acid vaccines against COVID-19” pertaining to repRNA-CoV-2S. J.H.E., A.K., and S.G.R. are co-inventors on US patent application no. 62/993,307 “Compositions and methods for delivery of RNA” pertaining to the LION formulation.

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Animals
Antigens
Humans
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