Technological advances in mRNA delivery and engineering for therapeutic cancer vaccines

Messenger RNA (mRNA) offers a powerful platform for therapeutic cancer vaccines. Several clinical trials targeting tumor-associated antigens and neoantigens have demonstrated promising immunological and clinical responses. For effective cancer vaccination, technologies for in vivo mRNA delivery and mRNA molecular design are essential. mRNA delivery systems, typically based on synthetic nanoparticles, are designed to protect mRNA from enzymatic degradation, facilitate its delivery to lymphoid organs and antigen-presenting cells, and stimulate innate immune responses to serve as adjuvants. To maximize the potential of these delivery systems, molecular design of the delivered mRNA is also critical. Strategies such as nucleoside modification, self-amplifying RNA, circular RNA, and hybridization-based mRNA engineering are employed to modulate the immunostimulatory properties of mRNA, extend the duration of antigen presentation, and introduce additional functionalities to the delivery systems. While technological advances in these areas have significantly contributed to the recent progress of mRNA cancer vaccines, current formulations, including widely used lipid nanoparticles (iLNPs), still have considerable room for improvement in terms of safety and efficacy. This has prompted vigorous research efforts to redesign iLNPs and explore non-lipid-based approaches. In this context, this review outlines the established foundational technologies and highlights ongoing research in mRNA delivery and engineering, with a focus on their biological and functional aspects.