LNP-RNA-mediated antigen presentation leverages SARS-CoV-2-specific immunity for cancer treatment
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.
Authors
- Pauline Hamon (ORCID: https://orcid.org/0000-0002-6776-1635)
- Diana D. Kang
- David W. McComb (ORCID: https://orcid.org/0000-0003-3763-9652)
- Yizhou Dong (ORCID: https://orcid.org/0000-0001-5786-0659)
- Zhengwei Liu (ORCID: https://orcid.org/0009-0003-5105-6709)
- Nadejda M. Tsankova (ORCID: https://orcid.org/0000-0002-5333-312X)
- Jinye Dai (ORCID: https://orcid.org/0000-0002-8497-3154)
- Yuebao Zhang (ORCID: https://orcid.org/0009-0000-7883-1937)
- Xucheng Hou (ORCID: https://orcid.org/0000-0001-7833-8704)
- Dinglingge Cao (ORCID: https://orcid.org/0009-0007-3776-7474)
- Binbin Deng (ORCID: https://orcid.org/0000-0002-4058-0738)
- Meng Tian (ORCID: https://orcid.org/0000-0001-7719-9896)
- Brian D. Brown (ORCID: https://orcid.org/0000-0002-3670-8778)
- Miriam Mérad (ORCID: https://orcid.org/0000-0002-4481-7827)
- Yonger Xue (ORCID: https://orcid.org/0000-0002-6022-2487)
- Darrell J. Irvine (ORCID: https://orcid.org/0000-0002-8637-1405)
- Ron Weiss
- Siyu Wang (ORCID: https://orcid.org/0000-0002-5990-8887)
- Chang Wang (ORCID: https://orcid.org/0009-0005-1630-9453)
- Haoyuan Li (ORCID: https://orcid.org/0000-0002-7030-8065)
- Kaiyuan Guo (ORCID: https://orcid.org/0009-0001-0621-9543)
- Leiming Wang (ORCID: https://orcid.org/0000-0002-6602-473X)
- Yichen Zhong (ORCID: https://orcid.org/0000-0003-3652-1257)
- Shi Du
- Eric Purisic
Institutions
- Allen Institute for Brain Science (US)
- Howard Hughes Medical Institute (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Tisch Hospital (US)
- The Ohio State University (US)
- Massachusetts Institute of Technology (US)
- Chongqing Medical University (CN)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1038/s41467-025-57149-2
- Citations
- 17
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 23.73
Funders
- National Institute of General Medical Sciences