biostudies-literatureChaudhary NNICHD NIH HHSNIBIB NIH HHSFoundation for the National Institutes of HealthFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)National Science Foundation (NSF)Wadhwani FoundationNational Science Foundation1483-1498https://www.ebi.ac.uk/biostudies/studies/S-EPMC11863198biostudies-literatureUnknown8(11)Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicle for RNA therapeutics, partly because of established lipid structure-activity relationships focused on formulation potency. Yet such knowledge has not extended to LNP immunogenicity. Here we show that the innate and adaptive immune responses elicited by LNPs are linked to their ionizable lipid chemistry. Specifically, we show that the amine headgroups in ionizable lipids drive LNP immunogenicity by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation. Immunogenic LNPs favour a type-1 T-helper-cell-biased immune response marked by increases in the immunoglobulins IgG2c and IgG1 and in the pro-inflammatory cytokines tumour necrosis factor, interferon γ and the interleukins IL-6 and IL-2. NotNature biomedical engineeringAmine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d.PMC11863198F32-EB029345DGE1745016DP2 HD098860F32 EB029345DP2-HD098860Arral MLChaudhary NLoPresti STFein KCStrelkova Petersen DMKasiewicz LNMelamed JRPurwar RNewby ANYerneni SSWhitehead KAKumar SfalseAmine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d.Lipid nanoparticles (LNPs) are the most clinically advanced delivery vehicle for RNA therapeutics, partly because of established lipid structure-activity relationships focused on formulation potency. Yet such knowledge has not extended to LNP immunogenicity. Here we show that the innate and adaptive immune responses elicited by LNPs are linked to their ionizable lipid chemistry. Specifically, we show that the amine headgroups in ionizable lipids drive LNP immunogenicity by binding to Toll-like receptor 4 and CD1d and by promoting lipid-raft formation. Immunogenic LNPs favour a type-1 T-helper-cell-biased immune response marked by increases in the immunoglobulins IgG2c and IgG1 and in the pro-inflammatory cytokines tumour necrosis factor, interferon γ and the interleukins IL-6 and IL-2. Not2024-01-01T00:00:00Z2024 Nov2026-06-05T09:24:07.756Z2026-05-15T03:12:57.661ZS-EPMC118631983936310610.1038/s41551-024-01256-w