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Publications

Journal Article Epublish 1 citation

PubMed: 40038251 DOI: 10.1038/s41467-025-57149-2

LNP-RNA-mediated antigen presentation leverages SARS-CoV-2-specific immunity for cancer treatment.

Nat Commun 16(1):2198

Authors: Yonger Xue, Xucheng Hou, Yichen Zhong, Yuebao Zhang, Shi Du, Diana D Kang, Leiming Wang, Chang Wang, Haoyuan Li, Siyu Wang, Zhengwei Liu, Meng Tian, Kaiyuan Guo, Dinglingge Cao, Binbin Deng, David W McComb, Eric Purisic, Jinye Dai, Pauline Hamon, Brian D Brown, Nadejda M Tsankova, Miriam Merad, Darrell J Irvine, Ron Weiss, Yizhou Dong

Affiliations

  • Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
  • Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, USA.
  • Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA.
  • Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Center for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
  • Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

Lipid nanoparticle (LNP)-mRNA vaccines have demonstrated protective capability in combating SARS-CoV-2. Their extensive deployment across the global population leads to the broad presence of T-cell immunity against the SARS-CoV-2 spike protein, presenting an opportunity to harness this immunological response as a universal antigen target for cancer treatment. Herein, we design and synthesize a series of amino alcohol- or amino acid-derived ionizable lipids (AA lipids) and develop an LNP-RNA-based antigen presentation platform to redirect spike-specific T-cell immunity against cancer in mouse models. First, in a prime-boost regimen, AA2 LNP encapsulating spike mRNA elicit stronger T-cell immunity against the spike epitopes compared to FDA-approved LNPs (ALC-0315 and SM-102), highlighting the superior delivery efficiency of AA2 LNP. Next, AA15V LNP efficiently delivers self-amplifying RNAs (saRNAs) encoding spike epitope-loaded single-chain trimer (sSE-SCT) MHC I molecules into tumor tissues, thereby inducing the presentation of spike epitopes. Our results show that a single intratumoral (i.t.) treatment of AA15V LNP-sSE-SCTs suppresses tumor growth and extends the survival of B16F10 melanoma and A20 lymphoma tumor-bearing mice vaccinated with AA2 LNP-spike mRNA. Additionally, AA15V LNP-sSE-SCTs enable SE-SCT expression in ex vivo human glioblastoma and lung cancer samples, suggesting its potential in clinical translation.

MeSH

Cells, Sars-Cov-2, Epitopes, Vaccines, Biological Science Disciplines, Neoplasms, Antigen Presentation, Immunity, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Rna, Lipid Nanoparticles

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