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.