AbstractPoly(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.