Lipid Nanoparticle Encapsulation Empowers Poly(I:C) to Activate Cytoplasmic RLRs and Thereby Increases Its Adjuvanticity

Alexander Lamoot, Sonia Jangra, Gabriel Laghlali, Prajakta Warang, Gagandeep Singh, Lauren A. Chang, Seok Chan Park, Gagandeep Singh, Kim De Swarte, Zifu Zhong, Benoit Louage, Emily De Lombaerde, Tingting Ye, Yong Chen, Sara Cuadrado-Castano, Stefan Lienenklaus, Niek N. Sanders, Bart N. Lambrecht, Adolfo García-Sastre, Michael SchotsaertBruno G. De Geest

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Poly(I:C) is a synthetic analogue of dsRNA capable of activating both TLR3 and RLRs, such as MDA-5 and RIG-I, as pathogen recognition receptors. While poly(I:C) is known to provoke a robust type I IFN, type III IFN, and Th1 cytokine response, its therapeutic use as a vaccine adjuvant is limited due to its vulnerability to nucleases and poor uptake by immune cells. is encapsulated poly(I:C) into lipid nanoparticles (LNPs) containing an ionizable cationic lipid that can electrostatically interact with poly(I:C). LNP-formulated poly(I:C) triggered both lysosomal TLR3 and cytoplasmic RLRs, in vitro and in vivo, whereas poly(I:C) in an unformulated soluble form only triggered endosomal-localized TLR3. Administration of LNP-formulated poly(I:C) in mouse models led to efficient translocation to lymphoid tissue and concurrent innate immune activation following intramuscular (IM) administration, resulting in a significant increase in innate immune activation compared to unformulated soluble poly(I:C). When used as an adjuvant for recombinant full-length SARS-CoV-2 spike protein, LNP-formulated poly(I:C) elicited potent anti-spike antibody titers, surpassing those of unformulated soluble poly(I:C) by orders of magnitude and offered complete protection against a SARS-CoV-2 viral challenge in vivo, and serum from these mice are capable of significantly reducing viral infection in vitro.

Original languageEnglish
Article number2306892
JournalSmall
Volume20
Issue number10
DOIs
StatePublished - 8 Mar 2024

Keywords

  • immunotherapy
  • innate immune receptors
  • lipid nanoparticles
  • vaccine adjuvants

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