SBIR Phase I: Leveraging Sequence-Structure-Function Relationships to Improve RNA Therapeutics

Award ID: 2538015

The broader and commercial impact of this Small Business Innovation Research (SBIR) Phase I project is the development of a new approach for improving the efficacy, durability, and safety of RNA medicines. RNA-based therapies often fail to achieve sustained effects in the body or trigger unwanted immune responses, limiting their usefulness for chronic and serious diseases such as autoimmune disorders, cancer, and genetic conditions. This project addresses these challenges by exploring new design strategies that enable therapeutic RNAs to function more predictably and for longer periods after administration. If successful, the work will strengthen the scientific foundation for next-generation RNA medicines that require fewer doses, reduce side effects, and are applicable across a broader range of disease indications. The innovation is expected to enhance scientific and technological understanding of RNA medicine by establishing generalizable design principles that link molecular structure with biological performance. From a societal perspective, the project supports improved health outcomes, reduced long-term healthcare costs, and increased preparedness for emerging medical needs. The activity also contributes to strengthening U.S.-based capabilities in the design and manufacturing of therapeutic RNAs. From a commercial perspective, the work lays the groundwork for scalable technologies that support economic growth, high-quality job creation, and U.S. leadership in advanced biotechnology. The proposed project addresses a fundamental technical barrier that limits the performance of therapeutic RNA molecules when they are chemically modified to improve stability and safety. Although such modifications are widely used, they can interfere with essential molecular functions, reducing effectiveness and reproducibility. The research objective of this Phase I effort is to identify and validate design strategies that preserve RNA function under these challenging conditions. The project will combine systematic molecular design, high-throughput experimental testing, and functional data-driven refinement to evaluate how RNA sequence and structural features influence performance. Experimental results will be quantitatively measured and used to guide iterative optimization. The anticipated technical outcomes include validated functional elements, performance benchmarks under modified conditions, and predictive design rules that inform future development. The scope of the research is limited to feasibility demonstration and technical risk reduction, providing a foundation for expanded development in a subsequent phase. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Program Director: Erik Pierstorff