mRNA-based therapeutic strategies for cancer treatment

Abstract

In the rapidly evolving landscape of medical research, the emergence of RNA-based therapeutics is paradigm shifting. It is mainly driven by the molecular adaptability and capacity to provide precision in targeting. The coronavirus disease 2019 pandemic crisis underscored the effectiveness of the mRNA therapeutic development platform and brought it to the forefront of RNA-based interventions. These RNA-based therapeutic approaches can reshape gene expression, manipulate cellular functions, and correct the aberrant molecular processes underlying various diseases. The new technologies hold the potential to engineer and deliver tailored therapeutic agents to tackle genetic disorders, cancers, and infectious diseases in a highly personalized and precisely tuned manner. The review discusses the most recent advancements in the field of mRNA therapeutics for cancer treatment, with a focus on the features of the most utilized RNA-based therapeutic interventions, current pre-clinical and clinical developments, and the remaining challenges in delivery strategies, effectiveness, and safety considerations.

Keywords: RNA delivery; biomarkers; cancer vaccines; immunotherapy; mRNA; therapy.

Graphical abstract

Figure 1

Types of RNA-based therap Illustrations of various types of RNA therapy, including siRNA, microRNA (miRNA), CRISPR-Cas9/Cas13, saRNA, ribozymes, ASOs, aptamer, and mRNA.

Figure 2

Modification of mRNA structure for therapeutic use mRNA is composed of an ORF carrying the code sequences, flanked by two UTRs. The 3′ end is adenylated forming the poly A tail and the 5′ end is capped by a modified guanine. In vitro transcribed mRNA can be engineered to express a wanted sequence, carry some post-transcriptional modifications or viral replicase to amplify mRNA translation in targeted cells.

Figure 3

LNP structure and formulation There are three types of lipids constituting LNPs: ionizable cationic lipids, zwitterionic PLs, and helper lipids. Various types of lipids can provide distinct features affecting encapsulation of mRNA, tissue targeting, cell delivery, and immunogenicity.

Figure 4

Mechanism of action of mRNA vaccine for cancer treatment LNPs carrying the therapeutic mRNA is delivered to the cell through endocytosis and translated into a protein using the host cell translation machinery. This protein can be secreted and enter the cell again and produce an antigen that will be presented on the class II MHC, activating CD4⁺ T cells and B cells, triggering an antibody-dependent immunity response. The protein can also go through proteasome degradation and the subsequent production of peptides can allow the loading of class I MHC and presentation of the antigen to cytotoxic LT CD8⁺.