The COVID-19 pandemic makes the mRNA vaccine become the focus of global researchers. The rapid development of the COVID-19 vaccine benefits from years of research on using mRNA vaccines as a cancer treatment strategy in preclinical and clinical trials. The advantages of mRNA in the process of vaccination are listed below:

First, mRNA vaccines are well tolerated, easy to degrade, and not easy to integrate into the host genome.

Second, the mRNA molecule is non-infectious and has the potential to stimulate humoral and cellular immunity.

Finally, mRNA vaccines have the advantages of fast production and low cost.

In 1996, the first mRNA-based cancer vaccine was first tested in vitro in dendritic cells (DCs). Nowadays, with the progress of science and technology, the structure, stability, and injection mode of mRNA have been optimized in many aspects. A number of clinical trials are recruiting cancer patients for mRNA vaccine treatment.

The administration of mRNA can be accomplished through intradermal, subcutaneous, intranasal, intranasal, intramuscular, intratumoral, and intravenous routes. In vitro engineering of autologous dendritic cells with mRNA has always been the preferred method for tumor antigen delivery. However, most mRNA vaccines are currently directly injected with lipid nanoparticles as carriers.

The clinical efficacy and immunogenicity of mRNA vaccines have been evaluated in cancer diagnosis and administration. Some experimental reports have shown that cancer patients developed long-lasting immunity after being treated with mRNA vaccines and had no uncontrollable side effects. The mRNA vaccine is a promising candidate for future cancer treatment, especially when used in combination with other immunotherapies. However, the ongoing mRNA cancer vaccine research has not reached the clinical III phase. At the time of publication of this article, no mRNA vaccine for cancer treatment has been approved. This paper summarizes the latest clinical progress of therapeutic mRNA cancer vaccines, with emphasis on the delivery mode of mRNA vaccines.

mRNA-Based Cancer Vaccine Trial

The purpose of mRNA vaccination is to induce or promote an effective anti-tumor immune response. Synthetic mRNA encoding tumor-associated or tumor-specific antigens are delivered by in vitro engineered autologous dendritic cells or by encapsulated or unencapsulated mRNA injection. After vaccination and uptake by antigen-presenting cells, mRNA is transported to the cytoplasm, and MHC cascades are induced after antigen treatment. Therefore, antigen-presenting cells can activate CD8+ and CD4+T cells after presenting tumor-associated antigens to MHC class I and MHC II. In addition, CD4+T cells can co-activate antigen-specific B cells and induce a humoral immune response. B cells, as antigen-presenting cells, can in turn activate CD4+T cells after internalizing extracellular proteins and presenting them to the MHC II class of B cells.

Unencapsulated (Naked) mRNA Cancer Vaccine

Naked or unencapsulated mRNA vaccines store mRNA molecules in a buffer solution, which can be injected intradermally or in nodules. Administration of naked mRNA in nodules can transfer antigens to antigen-presenting cells at the actual sites where T cells are activated, thus avoiding the need to resist the migration of progenitor cells. Many studies have shown that dendritic cells can absorb naked mRNA injected into nodules and produce an effective anti-tumor T cell response.

In the past five years, there have been only a few clinical trials using naked mRNA vaccines to treat cancer. Clinical trials registered with the website do not currently recruit patients for naked mRNA cancer vaccine treatment.

Encapsulated mRNA Cancer Vaccine

The naked mRNA is easily degraded by extracellular RNA enzymes. Therefore, scholars have developed several nano-carrier drug systems, which usually contain polymers such as peptides or lipids, to optimize mRNA preservation and promote mRNA uptake by antigen-presenting cells.

  • Protamine-encapsulated mRNA cancer vaccine

Protamine is a positively charged polycationic peptide that forms a complex with the negatively charged mRNA to protect molecules from degradation. Protamine-encapsulated mRNA vaccines have been evaluated in different clinical trials in the form of RNActive vaccines. RNA-active vaccines combine nucleotide-modified mRNA molecules with protamine to improve protein expression and immunogenicity. Currently, there are no clinical trials that have registered with and recruited patients to conduct clinical trials of protamine preparation mRNA cancer vaccine research.

  • mRNA-liposome vaccine

The mRNA-lipid vaccine is delivered using a mixed carrier that binds mRNA complexes and polycationic components in the lipid shell. Positively charged cationic lipids naturally form complexes with negatively charged mRNA and promote endocytosis of antigen-presenting cells, so they are commonly used in the construction of lipid complexes.