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

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 and Yizhou Dong ()
Additional contact information
Yonger Xue: The Ohio State University
Xucheng Hou: Icahn School of Medicine at Mount Sinai
Yichen Zhong: Icahn School of Medicine at Mount Sinai
Yuebao Zhang: The Ohio State University
Shi Du: The Ohio State University
Diana D. Kang: The Ohio State University
Leiming Wang: Icahn School of Medicine at Mount Sinai
Chang Wang: The Ohio State University
Haoyuan Li: Icahn School of Medicine at Mount Sinai
Siyu Wang: Icahn School of Medicine at Mount Sinai
Zhengwei Liu: Icahn School of Medicine at Mount Sinai
Meng Tian: Icahn School of Medicine at Mount Sinai
Kaiyuan Guo: Icahn School of Medicine at Mount Sinai
Dinglingge Cao: Icahn School of Medicine at Mount Sinai
Binbin Deng: The Ohio State University
David W. McComb: The Ohio State University
Eric Purisic: Icahn School of Medicine at Mount Sinai
Jinye Dai: Icahn School of Medicine at Mount Sinai
Pauline Hamon: Icahn School of Medicine at Mount Sinai
Brian D. Brown: Icahn School of Medicine at Mount Sinai
Nadejda M. Tsankova: Icahn School of Medicine at Mount Sinai
Miriam Merad: Icahn School of Medicine at Mount Sinai
Darrell J. Irvine: Massachusetts Institute of Technology
Ron Weiss: Massachusetts Institute of Technology
Yizhou Dong: The Ohio State University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57149-2

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