Authors
Jerala, R., Lainscek, D., Malensek, S., Golob-Urbanc, A., Orehek, S., Bohinc, J., Mancek Keber, M., Sotosek, T., Esih, H., Fortsneric, V., Pecan, P., Pantovic Zalig, J., Bencina, M., Bester, R., Protzer, U.
Abstract
Programmable nucleic-acid therapeutics, including lipid nanoparticle (LNP), formulated mRNA vaccines, genome editors delivered as mRNA, and viral vectors, are transforming precision medicine but remain constrained by innate reactogenicity despite the introduction of chemical modifications into mRNA. Here, we show that mRNA/LNPs and viral vectors elicit a transient inflammatory burst that peaks ~6 h after dosing in vivo. Coadministration or prophylaxis with hydroxychloroquine (HCQ), a clinically established 4aminoquinoline, potently attenuated cytokine and chemokine induction across modalities, including strong responses to unmodified mRNA, without compromising therapeutic efficacy. Humoral and cellular immunity to SARS-CoV-2 Spike mRNA vaccines (BNT162b2 and non-modified mRNA/LNP) were preserved, as was live-virus neutralization. Transcriptomic profiling indicated selective dampening of TLR/cGAS/STING pathways with retention of type I interferon elements compatible with effective vaccination. HCQ further mitigated AAV9 associated blood brain barrier (BBB) disruption after stereotactic delivery to the mouse brain and reduced mRNA/LNP associated hepatotoxicity and thrombocytopenia while maintaining therapeutic transgene expression and CRISPR base editing in vivo. These findings identify HCQ as an antireactogenic adjunct that widens the safety window of nucleic-acid therapeutics without sacrificing performance.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Nov 2025.
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