Dimethylamino-based synthetic lipidoid nanoparticles for selective mRNA delivery to splenic antigen-presenting cells.

Targeted systemic mRNA delivery to extrahepatic tissues remains a formidable challenge, especially in the absence of targeting ligands on lipid nanoparticles. In this study, we introduce a series of dimethylamino-based ionizable lipidoids (DMA-Lipidoids) engineered for selective mRNA delivery to the spleen. Using a combinatorial approach, we synthesized 48 chemically distinct lipidoids by pairing four DMA-containing amine heads with 12 newly designed hyperbranched tails. Remarkably, lipidoids with tails H228, H226x, H246x, and H446x demonstrated exceptional spleen-targeting efficiency. To refine the lipidoid design, we constructed and screened a secondary library of 36 lipidoids containing DMA analogues. Through this two-round screening process, we identified lipidoids with both high potency and spleen selectivity. The lead candidate, DMA4-H228, achieved precise delivery of ovalbumin mRNA to antigen-presenting cells (APCs), driving interferon-α (IFN α) production and APC activation. This robust immune response effectively inhibited tumor growth. Overall, these innovative DMA-lipidoids demonstrate strong spleen-targeting capabilities, offering a transformative platform for mRNA vaccine development.