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Circular RNAs (circRNAs) have progressed from being viewed as splicing by-products to emerging therapeutic constructs with a distinct pharmacology. Their covalently closed topology can increase RNA stability, prolong intracellular persistence, and under some conditions sustain translation relative to matched linear RNAs. However, circRNA performance and immunogenicity depend strongly on the circularisation chemistry, impurity profiles (linear RNA and double-stranded RNA (dsRNA) by-products), sequence and structural features, and the delivery formulation. Consequently, broad claims such as 'circRNA is less immunogenic than mRNA' are unreliable without rigorous, standardised benchmarking. This narrative review provides a conceptually grounded, evidence-informed synthesis of recent advances in synthetic (exogenous) circRNA therapeutics across oncology, immunology (including vaccines), and rare/chronic diseases. We combine structured literature identification (2018-November 2025) with qualitative appraisal of preclinical and early translational studies, focusing on: (i) platform engineering (circularisation, purification, translation elements, and delivery); (ii) therapeutic modality (protein-coding versus regulatory circRNAs and programmable circuits); (iii) disease-domain use cases; and (iv) unresolved controversies and translational constraints. We introduce a decision-oriented three-axis framework to delineate settings in which circRNA plausibly offers added value (for example, single-dose local protein depots; durable antigen expression for selected vaccine strategies) versus contexts where evidence remains preliminary or advantages may diminish when compared against optimised mRNA/self-amplifying RNA (saRNA) comparators. We also highlight emerging computational models that may accelerate circRNA target and drug-sensitivity discovery. Finally, we propose priorities for the field: standardised purity and identity assays, head-to-head platform comparisons, mechanistic immunoprofiling, and indication-focused early clinical development.
Ugwu et al. (Tue,) studied this question.