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

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

  • J Control Release. 2025 Jun 10:382:113737. doi: 10.1016/j.jconrel.2025.113737.
Xue Liang 1,  Chenchen Zhang 1,  Qimeng Yin 1,  Yuerong Bai 1,  Jiahao Li 1,  Min Qiu 2
Affiliations

Affiliations

  • 1 Center for Medical Research and Innovation, Shanghai Pudong Hospital, Human Phenome Institute, Fudan University, Shanghai 201203, China.
  • 2 Center for Medical Research and Innovation, Shanghai Pudong Hospital, Human Phenome Institute, Fudan University, Shanghai 201203, China; Center for mRNA Translational Research, Fudan University, Shanghai 200438, China; Zhangjiang mRNA Innovation and Translation Center, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 40233831 DOI: 10.1016/j.jconrel.2025.113737
Abstract

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.

Keywords

Cancer vaccine; Lipid nanoparticles; Spleen-selective delivery; mRNA.

Figures
Products