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Albumin-recruiting lipid nanoparticle potentiates the safety and efficacy of mRNA vaccines by avoiding liver accumulation

Nature Materials volume 24, pages 1826–1839 (2025)Cite this article

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An Author Correction to this article was published on 12 August 2025

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Abstract

The advent of mRNA vaccines represents a breakthrough in the realm of cancer therapy and the prevention of infectious disease. Nevertheless, traditional lipid nanoparticle (LNP)-based mRNA vaccines can accumulate in the liver post-intramuscular injection, posing a risk of hepatotoxicity and reducing efficacy. Here we develop an albumin-recruiting LNP system with high lymphatic drainage and no accumulation in hepatic tissue to potentiate the efficacy and safety of mRNA vaccines. We construct a library of ionizable lipids with albumin-binding capacity as alternatives to traditional polyethylene-glycol-conjugated lipid. We identify an Evans blue-modified lipid-based LNP (EB-LNP) formulation that shows high in vivo expression, albumin-facilitated transport through intramuscular lymphatic vessels to the lymph nodes, high internalization by dendritic cells and low penetration into intramuscular blood vessels, thereby avoiding liver accumulation. EB-LNP-based mRNA vaccines demonstrate excellent antitumour and antiviral efficacy, resulting in strong cellular and humoral immune responses, including the robust activation of cytotoxic T lymphocytes and production of neutralizing antibodies post-vaccination. Overall, this system shows promise as an effective and minimally toxic platform for the development of mRNA vaccines with high efficacy and safety.

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Fig. 1: Mechanistic comparison of different LNP systems.
Fig. 2: Synthesis and formula optimization.
Fig. 3: Biodistribution pattern investigation in animal models.
Fig. 4: PC-dependent endocytosis and transport behaviour.
Fig. 5: Cellular immune responses in tumour models.
Fig. 6: Humoral immune responses in infectious disease models.

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Data availability

All relevant data of this study are available within the Article and its Supplementary Information. All proteomics raw data are deposited to the ProteomeXchange (https://proteomecentral.proteomexchange.org/cgi/GetDataset) with the identifier PXD061738. Source data are provided with this paper.

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Acknowledgements

We thank S. Zhu from the State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, Jilin University, for his valuable suggestions and technical assistance with NIR-II imaging. G.Y. acknowledges financial support from the Beijing Municipal Science & Technology Commission (Z231100007223007), the National Key R&D Program of China (2023YFE0204900 and 2023YFC3403100), the National Natural Science Foundation of China (22175107 and 22305140) and the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (SN-ZJU-SIAS-006). X.C. acknowledges financial support from the National University of Singapore (NUHSRO/2020/133/Startup/08, NUHSRO/2023/008/NUSMed/TCE/LOA, NUHSRO/2021/034/TRP/09/Nanomedicine, NUHSRO/2021/044/Kickstart/09/LOA and 23-0173-A0001), National Medical Research Council (MOH-001388-00, CG21APR1005, MOH-001500-00 and MOH-001609-00), Singapore Ministry of Education (MOE-000387-00 and MOET32023-0005) and National Research Foundation (NRF-000352-00). G.C. acknowledges financial support from the National Key R&D Program of China (2023YFC2305900, 2021YFC2300200, 2022YFC2303200, 2021YFC2302405, 2022YFC2303400 and 2023YFC2305902), the Shenzhen Medical Research Fund (B2404002), the Yunnan Major Scientific and Technological Projects (202502AU100001), Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases (SZSM202211023), Yunnan Provincial Science and Technology Project at Southwest United Graduate School (202302AO370010) and the New Cornerstone Science Foundation.

Author information

Author notes

  1. These authors contributed equally: Yunxuan Feng, Wanbo Tai, Pei Huang.

Authors and Affiliations

  1. Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China

    Yunxuan Feng, Shaolong Qi, Xinyang Yu, Mengfei Li, Mengyao Li, Xiaomin Gao, Kai Yang, Bing Bai, Jiaqi Lei, Meiqi Cheng, Yongcan Li & Guocan Yu

  2. Engineering Research Center of Advanced Rare Earth Materials, Department of Chemistry, Tsinghua University, Beijing, China

    Yunxuan Feng, Shaolong Qi, Xinyang Yu, Mengfei Li, Mengyao Li, Xiaomin Gao, Kai Yang, Bing Bai, Jiaqi Lei, Meiqi Cheng, Yongcan Li & Guocan Yu

  3. New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, China

    Wanbo Tai & Gong Cheng

  4. Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, China

    Wanbo Tai, Gong Cheng & Xiaoyuan Chen

  5. Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Pei Huang, Miya Zhang, Fangfang Cao & Xiaoyuan Chen

  6. Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Pei Huang, Fangfang Cao & Xiaoyuan Chen

  7. Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore

    Miya Zhang & Xiaoyuan Chen

  8. Department of Biomedical Engineering and Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  9. Clinical Imaging Research Centre, Centre for Translational Medicine, Nanomedicine Translational Research Program, Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  10. Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  11. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore

    Xiaoyuan Chen

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Contributions

Y.F., G.C., X.C. and G.Y. conceived and designed the research. Y.F., W.T., P.H., S.Q., X.Y., Mengyao Li, X.G. and K.Y. conducted the experiments. Y.F., Mengfei Li, M.Z., F.C., B.B., J.L., M.C. and Y.L. interpreted the data and developed the discussion. Y.F., X.C. and G.Y. composed the paper.

Corresponding authors

Correspondence to Gong Cheng, Xiaoyuan Chen or Guocan Yu.

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Extended data

Extended Data Fig. 1 Biodistribution pattern study.

a, In vivo fluorescence imaging of mice after i.m. injection of DiR-labeled EB-LNP@mRNALuci or DiR-labeled PEG-LNP@mRNALuci in the right thigh. b, Quantification of the fluorescence signal from abdomen in a. c, Quantification of the fluorescence signal from muscle in a. d, Percentages of DiR+ cells in mice inguinal LNs by FCM analysis. e, Percentages of DiR+ cells in mice liver tissues by FCM analysis. f, Ex vivo fluorescence imaging of rabbit main organs 4 h post-injection. Abbreviations: M, muscle; LNs, lymph nodes; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney. g, Immunofluorescence staining of mice LNs. Scale bar = 20 μm. Staining was repeated in n = 3 mice. Data in b–e were presented as mean ± s.d. from n = 3 biologically independent samples. Statistical significance was determined by one-way ANOVA with Dunnett’s multiple comparisons test: n.s., not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 2 Time-lapse imaging of main organs.

a, Ex vivo bioluminescence imaging of main organs at different time point post i.m. injection of DiR-labeled EB-LNP@mRNALuci or DiR-labeled PEG-LNP@mRNALuci. b, Ex vivo fluorescence imaging of main organs at different time point post i.m. injection of DiR-labeled EB-LNP@mRNALuci or DiR-labeled PEG-LNP@mRNALuci. Abbreviations: M, muscle; LN, lymph node; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney. c, CLSM images of the inguinal LNs at different times post i.m. injection of DiR-labeled EB-LNP@mRNAGFP or DiR-labeled PEG-LNP@mRNAGFP. Scale bar = 300 μm. Staining was repeated in n = 3 mice. d, The content of GFP in the LNs at different time points by ELISA. e, The content of DiR in the LNs at different time points by LC-MS. Data in d and e were presented as mean ± s.d. from n = 3 biologically independent samples. Statistical significance was determined by one-way ANOVA with Dunnett’s multiple comparisons test: n.s., not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 3 Albumin receptor mediated-endocytosis.

a–c, FCM analysis of endocytosis behavior in DC2.4 cells under various cultivation conditions following incubation with DiR-labeled EB-LNP@mRNAGFP or DiR-labeled PEG-LNP@mRNAGFP: in complete RPMI culture medium (a); in serum-free RPMI culture medium (b); in serum-free RPMI culture medium supplemented with BSA (c). d–f, Statistical diagrams of mean fluorescence intensity in a–c. g–i, Quantitative assessment of GFP+ DC2.4 cells under different cultivation conditions: in complete RPMI culture medium (g); in serum-free RPMI culture medium (h); in serum-free RPMI culture medium supplemented with BSA (i). j–l, Quantitative assessment of OVA-antigen peptide presentation in DC2.4 cells after incubation with EB-LNP@mRNAOVA or PEG-LNP@mRNAOVA: in complete RPMI culture medium (j); in serum-free RPMI culture medium (k); in serum-free RPMI culture medium supplemented with BSA (l). Data in d–l were presented from n = 3 biologically independent samples. Statistical significance was determined by one-way ANOVA with Dunnett’s multiple comparisons test: n.s., not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. For d–l, the center line represented the median, and the whiskers represented the maximum and minimum values.

Source data

Extended Data Fig. 4 Intramuscular transport pathway investigation by NIR-II imaging.

a, In vivo NIR-II fluorescence imaging of the mice post i.m. administration of ICG-labeled EB-LNP or ICG-labeled PEG-LNP. The white arrow indicated the initial injection site at right thigh. The blue arrowhead indicated illuminated blood vessels. The pink arrowhead indicated illuminated lymphatic vessels. The blue arrow pointed to the liver and the pink arrow pointed to inguinal LNs. b, In vivo NIR-II fluorescence imaging of the mice, which underwent thoracic duct ligation surgery post i.m. administration of ICG-labeled EB-LNP and ICG-labeled PEG-LNP. c,d, Quantitative analysis of the fluorescence signal intensity in lymphatic vessels (c) and blood vessels (d). e,f, Quantitative analysis of the fluorescence signal intensity in lymphatic vessel (e) and blood vessel (f) from the mice which underwent thoracic duct ligation surgery. g, Ex vivo NIR-II fluorescence imaging of the main organs 4 h post-injection. h, Quantitative analysis of the fluorescence signal intensity from main organs in g. i, Ex vivo NIR-II fluorescence imaging of the main organs from the mice underwent thoracic duct ligation surgery 4 h post-injection. j, Quantitative analysis of the fluorescence signal intensity from main organs in i. Abbreviations: M, muscle; LN, lymph node; H, heart; Li, liver; S, spleen; Lu, lung; K, kidney. Data in c–f, h, and j were presented as mean ± s.d. from n = 3 biologically independent samples. Statistical significance was determined by one-way ANOVA with Dunnett’s multiple comparisons test: n.s., not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Source data

Extended Data Fig. 5 Biosafety and immune responses investigation.

a–h, Liver functions assessment of the mice with different treatments: the levels of ALT (a), ALP (b), AST (c), γ-GT (d), TBIL (e), DBIL (f), ALB (g), and TBA (h). The area between the two gray dashed lines represented the normal range (NR). i,j, Detection of PEG-specific antibodies including IgM (i) and IgG (j) in mice serum. k–m, Liver tissues staining: ORO staining for lipid accumulation (k), DHE staining for intracellular reactive oxygen species (l), and H&E staining for pathological features (m). All scale bars = 100 μm. In a–m, C57BL/6 normal mice received three i.m. injections of EB-LNP or PEG-LNP on day 0, 3, and 5. The blood samples and livers were collected on day 6 to determine liver functions. PEG-specific antibodies in serum were continuously monitored until day 28. n–p, FCM analysis of inguinal LNs dissected from C57BL/6 normal mice 7 days after a single i.m. injection of EB-Vax or PEG-Vax: the percentages of CD11c+ DCs (n), CD11c+H2Kb+ DCs (o), and CD11c+CD80+CD86+ DCs (p). q, Determination of CD8+IFN-γ+ T cells in spleen. Abbreviations: EB-Vax for EB-LNP@mRNAOVA, and PEG-Vax for PEG-LNP@mRNAOVA. Data in a–j and n–q were presented as mean ± s.d. from n = 3 biologically independent samples. Statistical significance in a–h and n–q was determined by one-way ANOVA with Tukey’s correction: n.s., not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Statistical significance in i and j was determined by one-way ANOVA with Dunnett’s multiple comparisons test: n.s., not significant, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. For a–h and n–q, the center line represented the median, and the whiskers represented the maximum and minimum values.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Figs. 1–73, Discussion, Methods and references.

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Supplementary Video 1 (download MP4 )

EB-LNP in an i.m. blood vessel.

Supplementary Video 2 (download MP4 )

EB-LNP in an i.m. lymphatic vessel.

Supplementary Video 3 (download MP4 )

PEG-LNP in an i.m. blood vessel.

Supplementary Video 4 (download MP4 )

PEG-LNP in an i.m. lymphatic vessel.

Supplementary Video 5 (download MP4 )

Tissue clearing and imaging of the LN after the i.m. injection of EB-LNP.

Supplementary Video 6 (download MP4 )

Tissue clearing and imaging of the LN after the i.m. injection of PEG-LNP.

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Feng, Y., Tai, W., Huang, P. et al. Albumin-recruiting lipid nanoparticle potentiates the safety and efficacy of mRNA vaccines by avoiding liver accumulation. Nat. Mater. 24, 1826–1839 (2025). https://doi.org/10.1038/s41563-025-02284-w

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