My work addresses this fundamental challenge by pioneering an ‘immune-evasive’ saRNA platform that intrinsically silences the immune alarms it would normally trigger. By engineering the saRNA to co-express a suite of inhibitors that disarm the cell’s ability to detect it, the saRNA can replicate without provoking a harmful immune response. In mouse cells relevant to joint disease, I have demonstrated that this approach enables long-lasting, high-level protein expression with with minimal damage to the cells and reduced inflammatory mediator release.

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In contrast, conventional saRNA triggers immune responses that halt protein production, kill cells, and cause inflammation. While medications that suppress the immune system can reduce these reactions, they complicate treatment and increase the risk of infections and other complications. Unlike conventional saRNA, the immune-evasive saRNA platform operates without the need for external immunosuppressants. Additionally, I have shown that a small-molecule antiviral can serve as an ‘off-switch’ for this system, enabling controlled termination of gene expression after therapeutic goals are met and providing an important safety measure.

This proof-of-concept study in mouse cells demonstrates the potential of the immune-evasive saRNA platform to achieve long-term therapeutic gene expression by merging the established safety of mRNA with the durability of viral vectors.

My future work will focus on advancing this platform toward clinical use. The first step is to understand and overcome immune barriers caused by effector immune cells, which can attack treated cells and limit how long the saRNA remains in the body. These efforts will lead to improved immune-evasive saRNA designs that enable repeated dosing. At the same time, I will adapt the system for human cells by applying computational design to develop inhibitors that specifically target human immune proteins. Ultimately, the goal is to use this platform to develop new treatments, such as turning a patient’s own cells into “bio-factories” that continuously produce peptide therapeutics to help manage chronic diseases such as arthritis and autoimmune disorders.