Fig. 3: Risk factors and the cytotoxic mechanisms of mRNA vaccines.

A LNP-induced immune activation. Schematic structure of mRNA encapsulated into LNP formulations composed of an ionizable cationic lipid, helper lipid, cholesterol, and PEG. LNPs can induce immune activation by stimulating Toll-like receptor (TLR) 2 and TLR4 and leading to NF-kB activation and cytokine secretion. Preexisting anti-PEG antibodies can lead to complement activation and subsequently complement-mediated phenomena, such as ABC or CARPA. B LNP-encapsulated mRNA is taken up by immune cells through endocytosis. In endosomes, TLR7/8 and TLR3 recognize ssRNA and dsRNA, respectively, and the receptors activate MyD88 and TLR3 in Toll-interleukin-1 domain-containing adapter-inducing interferon (TRIF). Eventually, the related signaling cascades transduce to the nucleus where type I IFN and pro-inflammatory cytokine production is promoted by transcription factors (NF-kB, IRF3, and IRF7). Endosomal escape is used to transport small amounts of mRNA and IVT reaction byproducts to the cytoplasm. The RNAs are recognized by RIG-I and MDA5 and then both signaling pathways activate the transcription factors for inflammatory gene expression.