Core mission: mRNA endosomal escape

Abstract

As a promising therapeutic tool, messenger RNA (mRNA) must be directed toward specific subsets of cells, enter them, and be translated into proteins. Yet this journey is not without biological barriers. For scientists aiming to use mRNA to treat tumours, it must overcome insufficient endosomal escape. This problem occurs when our cells encounter exogenous materials, including naked mRNA, and sequester them in endosomal vesicles to be degraded. To avoid being trapped, therefore, mRNA needs to be encapsulated in specialized delivery vehicles to achieve endosomal escape for protein translation.

With these RNCs, the research group can now escort mRNA to its destination and observe in vitro how effective the mRNA therapy is. They delivered RNCs carrying a reporter mRNA to a macrophage cell line that serves as a model for TAMs, where RNCs surpassed a commonly used commercial transfection agent by producing more reporter protein. Moreover, they investigated and confirmed that adding endosomal escape-enhancing small molecules to the mRNA payload would further boost mRNA endosomal escape. However, incorporating these small molecules to the RNCs increased dose-dependent cellular toxicity.