Engineering lipid nanoparticle-stabilized emulsions for spatiotemporal mRNA delivery and enhanced T cell immunity

  • Cell Rep Med. 2026 Mar 17;7(3):102667. doi: 10.1016/j.xcrm.2026.102667.
Yan Zhou  1 ,  Weixiang Gao  1 ,  Xiaonan Huang  1 ,  Yumeng Yan  1 ,  Sihua Wu  2 ,  Xiangfei Shan  1 ,  Shaoyi Chen  3 ,  Mantang Qiu  3 ,  Guanghui Ma  1 ,  Yufei Xia  4
Affiliations
  • 1. National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2. National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China.
  • 3. Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Department of Thoracic Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China.
  • 4. National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 41850240 DOI: 10.1016/j.xcrm.2026.102667
Abstract

Achieving strong T cell responses remains a key challenge in mRNA vaccines and therapeutics. Here, we develop a colloid-engineered, lipid nanoparticle-stabilized emulsion (LSE) to study how spatiotemporal mRNA delivery influences immune dynamics. Multi-omic analyses (single-cell RNA Sequencing [scRNA-seq], flow cytometry, and enzyme-linked immunosorbent assay [ELISA]) illustrate that LSE facilitates localizing mRNA to immunocytes, increasing antigen presentation while reducing off-target antigen secretion, and non-immune cell cross-presentation, which are key factors linked to T cell exhaustion in conventional LNP-based systems. This targeted delivery induces durable interferon (IFN)-γ+ and interleukin (IL)-2+ T cell responses lasting up to 300 days and expands the T cell repertoire in mice compared to the AS01-adjuvanted Shingrix vaccine. Furthermore, LSE elicits potent protective and therapeutic effects against B16-OVA and LLC-NY-ESO1 inoculation in mice. These results indicate the potential of spatially controlled mRNA delivery for enhanced mRNA vaccinations.

Keywords
LSE; Pickering emulsion; T cell immunity; VZV vaccine; cancer vaccine; lipid nanoparticle-stabilized emulsion; mRNA vaccine; spatiotemporal mRNA delivery.
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