Background

Conventional messenger RNA (mRNA) vaccines rely on the cellular translation of the vaccine's genetic information into protein antigens. In cancer immunotherapy, it is common to co-administer an adjuvant that stimulates the intracellular 'Stimulator of Interferon Genes (STING)' pathway to enhance the immune response. This pathway induces a potent type I interferon response, which activates CD8+ T cells that attack cancer cells. However, simultaneously delivering mRNA and a STING adjuvant within a lipid nanoparticle (LNP) can create a significant problem. The adjuvant, once inside the cell, immediately activates STING, which forcibly halts the protein translation system. This results in the premature termination of vaccine function before the antigen can be produced, significantly reducing vaccine efficacy. Furthermore, uncontrolled STING activation can lead to serious side effects, such as the dysregulation of B cell differentiation and immune cell apoptosis.

Key Findings

The research team at Peking University, led by Professor Lei Miao, developed a 'Syn-STING' platform that synchronizes antigen translation and immune stimulation with a time delay. This platform involves co-delivering antigen mRNA, STING protein mRNA, and a delayed-release STING adjuvant (DMXAA) attached to a biodegradable linker within a single LNP. Initially, the adjuvant remains inactive, allowing cells to fully synthesize the antigen. Subsequently, the LNP degrades, releasing the adjuvant and activating the STING pathway. At the same time, the released STING mRNA amplifies protein production, maximizing the immune response. The research team administered this to a humanized STING mouse model that responds to DMXAA. The Syn-STING LNP selectively entered myeloid cells, including dendritic cells and macrophages. Because antigen expression is ensured and localized STING activation is induced, no harmful immune toxicity was observed. In an animal study targeting the human papillomavirus (HPV) E7 antigen, the number of regulatory B cells decreased, while Th1 T cell immunity increased, leading to tumor control and increased survival. The LNP also exhibits practical advantages, such as a low antibody response, allowing for repeated vaccinations.

Significance and Prospects

This study demonstrates, for the first time, the design principle that controlling the rate of adjuvant stimulation is crucial for enhancing the efficacy of mRNA cancer vaccines. It proposes an approach to physically separate antigen production and immune activation to create a highly effective vaccine. As a result, STING pathway-activating drugs, which have been criticized for interfering with antigen translation, may now be widely used in mRNA-based platforms. Further improvements are needed for clinical application. The experimental substance, DMXAA, acts only in mice; therefore, a new chemical derivative that activates human STING and a corresponding LNP manufacturing method need to be established. Precise research is needed to accurately measure and control the timing of LNP degradation and the release of active substances in the human cancer microenvironment.