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Life sciences · Journal article
Frontiers in Biomaterials Science · October 16, 2026
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Circular RNAs (circRNAs) are covalently closed RNA molecules with exceptional intrinsic stability and when properly designed, purified, nucleoside-modified, and delivered, show reduced unwanted innate immune activation, endowing them with unique advantages for vaccines, cancer immunotherapy, and protein replacement therapies. Synthetic circRNAs can be generated via enzymatic ligation, chemical ligation, or ribozyme-mediated circularization; however, efficient translation and scalable manufacturing remain major bottlenecks. In this Review, we survey current production strategies and therapeutic applications of synthetic circRNAs, and delineate engineering approaches that enhance molecular stability through nucleoside modification and sequence optimization, as well as strategies to improve translational efficiency, including internal ribosome entry site (IRES) and cap-mimicking elements, epitranscriptomic modifications, and rational sequence design. We further examine how these optimizations intersect with immunogenicity and process development, highlighting the critical quality attributes that govern circRNA product consistency and performance. Finally, we discuss emerging opportunities for algorithm-driven design and integrated engineering platforms, emphasizing their potential to accelerate the clinical translation of circRNA therapeutics.