As an alternative to conventional lipid nanoparticles (LNPs), Zhou, Gao, Huang, and Yan et al. developed a colloid-engineered, LNP-stabilized emulsion (LSE) that was preferentially taken up by APCs (rather than stromal cells or fibroblasts), enhancing chemokine-driven activation and localized antigen presentation while reducing off-target antigen expression and non-immune cell cross-presentation. LSE fostered Th1-polarizization, expanded the T cell repertoire, and increased IFNγ and IL-2, with responses lasting up to 300 days. In murine tumor models, LSE vaccines elicited protective and therapeutic antitumor immunity that enhanced survival.
Contributed by Lauren Hitchings
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.
Author Info: (1) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical E
Author Info: (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; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (3) 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. (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. (5) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China. (6) 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. (7) 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. (8) 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. (9) 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. (10) 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: yfxia@ipe.ac.cn.
