From structural design to delivery: mRNA therapeutics for cancer immunotherapy

Abstract

AbstractmRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence‐known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen‐presenting cells (APCs) can synthesize mutant neo‐antigens and multi‐antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T‐cell receptor (TCR), CD134, and immune‐modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large‐scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA‐based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA‐based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA‐based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA‐based cancer immunotherapy are also discussed.

Recent advanced lipid-based nanomedicines for overcoming cancer resistance

“…During the global outbreak of COVID-19, Comirnaty® and Spikevax® are mRNAencapsulated LNPs for COVID-19 vaccination with FDA approvals in 2020 and 2021, respectively. mRESVIA (mRNA-1345), an mRNA respiratory syncytial virus (RSV) vaccine based on the Spikevax® platform, is also approved by the U.S. FDA in 2024 [121,122] . LNPs have rapidly drawn robust attention as an effective tool for transporting and protecting genetic materials into cells [60,123,124] .…”

“…mRESVIA (mRNA-1345), an mRNA respiratory syncytial virus (RSV) vaccine based on the Spikevax® platform, is also approved by the U.S. FDA in 2024 [ 121 , 122 ] . LNPs have rapidly drawn robust attention as an effective tool for transporting and protecting genetic materials into cells [ 60 , 123 , 124 ] . Interestingly, as a representative milestone, the RNA-LNPs systems of anticancer drugs were examined and administrated to patients with cancer before the massive attention of the RNA-LNPs-based COVID-19 vaccines [ 125 ] .…”