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. Notably, the inflammatory signals originating from these receptors inhibit the production of anti-poly(ethylene glycol) IgM antibodies, preventing the often-observed loss of efficacy in the LNP-mediated delivery of siRNA and mRNA. Moreover, we identified computational methods for the prediction of the structure-dependent innate and adaptive responses of LNPs. Our findings may help accelerate the discovery of well-tolerated ionizable lipids suitable for repeated dosing.

脂质纳米颗粒 （LNP） 是临床上最先进的 RNA 治疗递送载体，部分原因是已建立的脂质结构-活性关系侧重于制剂效能。然而，这些知识尚未扩展到 LNP 免疫原性。在这里，我们表明 LNP 引发的先天性和适应性免疫反应与其可电离的脂质化学有关。具体来说，我们表明可电离脂质中的胺头基通过与 Toll 样受体 4 和 CD1d 结合以及促进脂筏形成来驱动 LNP 免疫原性。免疫原性 LNP 有利于 1 型 T 辅助细胞偏向性免疫反应，其特征是免疫球蛋白 IgG2c 和 IgG1 以及促炎细胞因子肿瘤坏死因子、干扰素 γ 以及白细胞介素 IL-6 和 IL-2 的增加。值得注意的是，源自这些受体的炎症信号抑制了抗聚乙二醇 IgM 抗体的产生，从而防止了在 LNP 介导的 siRNA 和 mRNA 递送中经常观察到的疗效丧失。此外，我们确定了预测 LNPs 结构依赖性先天性和适应性反应的计算方法。我们的研究结果可能有助于加速发现适合重复给药的耐受性良好的可电离脂质。