Traditional biomarkers, including many protein-based indicators, often fail to capture the dynamic regulatory changes that drive disease progression and influence treatment responses. Although Circular RNAs (circRNAs) are exceptionally stable, highly tissue-specific, and readily detectable in blood and other biofluids, their clinical adoption has been slow. Key barriers include the absence of standardized measurement methods, variability in RNA extraction protocols, and lingering uncertainty about whether many circRNAs are truly functional or merely splicing noise. Based on these challenges, deeper investigation into circRNA biology, standardized detection pipelines, and therapeutic engineering is urgently needed to unlock their full clinical potential.
A team at Sunnybrook Research Institute and the University of Toronto has published (DOI: 10.1093/pcmedi/pbag011) a comprehensive review in Precision Clinical Medicine (2026, Volume 9, Issue 2). The work outlines how circRNAs can be selectively targeted at both the RNA and protein levels, offering a dual-layer approach to intervention. The authors also examine how synthetic circRNAs are being engineered as stable, programmable therapeutics, and they discuss the delivery systems—from lipid nanoparticles to viral vectors—that will be essential for bringing these treatments into clinical practice.
The review highlights multiple innovative strategies now under development. Antisense oligonucleotides designed to target unique back-splice junctions can suppress disease-driving circRNAs without disturbing their cognate linear messenger RNAs, solving a major specificity problem. CRISPR-Cas13 systems offer programmable RNA degradation and have been successfully applied in large-scale circRNA screening platforms. Meanwhile, engineered synthetic circRNAs—delivered via lipid nanoparticles or adeno-associated virus vectors—can produce sustained protein expression that often outlasts conventional messenger RNA therapies. Remarkably, some circRNAs undergo rolling-circle translation, generating repetitive protein products, as shown for circEGFR in glioblastoma, where the resulting protein variant sustains tumor-driving signaling. Others, such as a peptide encoded by circCDYL, exacerbate cardiac hypertrophy, while a protein derived from circFBXW7 suppresses glioma tumorigenesis. The authors also emphasize circRNAs’ clinical potential as liquid biopsy biomarkers. For example, plasma levels of hsa_circ_0000190 correlate with immunotherapy response in lung cancer, and serum circAHSA1 tracks gastric cancer progression and lymph node metastasis. Importantly, the first human trial of a circRNA therapeutic—RXRG001 for radiation-induced dry mouth—is already underway, marking a major translational milestone.
“What excites us most is that circRNAs combine stability, specificity, and function in one single package,” the authors said. “They’re not just molecular sponges anymore—many of them actually produce proteins that actively drive disease. That gives us two distinct ways to intervene: we can knock down the circular RNA itself, or we can go after the protein it makes. And because their closed-loop structure resists breakdown, they’re ideal for long-lasting therapies or as stable biomarkers you can easily detect from a simple blood test. We’re really just beginning to explore what they can do.”
These findings pave the way for circRNA-based diagnostics and therapeutics across oncology, cardiology, and neurology. Liquid biopsy panels measuring circulating circRNAs could enable early cancer detection, real-time treatment monitoring, and risk stratification for heart failure patients. Engineered circRNAs expressing therapeutic proteins offer durable, low-immunogenicity alternatives to messenger RNA vaccines and protein replacement therapies. Looking ahead, artificial intelligence-driven tools may help predict which circRNAs are truly translatable, accelerating target discovery and validation. As delivery systems continue to improve, circRNA drugs could become a mainstay of precision medicine—closing the loop from non-invasive diagnosis to targeted, durable treatment in a single molecular platform.
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References
DOI
10.1093/pcmedi/pbag011
Original Source URL
https://doi.org/10.1093/pcmedi/pbag011
Funding Information
Our study was supported by The Lotte and John Hecht Memorial Foundation (grant No. 20250902).
About Precision Clinical Medicine
Precision Clinical Medicine (PCM) commits itself to the combination of precision medical research and clinical application. PCM is an international, peer-reviewed, open-access journal that publishes original research articles, reviews, clinical trials, methodologies, opinions in the field of precision medicine in a timely manner. By doing so, the journal aims to provide new theories, methods, and evidence for disease diagnosis, treatment, prevention and prognosis, so as to establish a communication platform for clinicians and researchers that will impact practice of medicine. The journal covers all aspects of precision medicine, which uses novel means of diagnosis, treatment and prevention tailored to the needs of a patient or a sub-group of patients based on the specific genetic, phenotypic, or psychosocial characteristics. Clinical conditions include cancer, infectious disease, inherited diseases, complex diseases, rare diseases, etc. The journal is now indexed in ESCI, Scopus, PubMed Central, etc., with an impact factor of 5.0 (JCR2024, Q1). For further information, please refer to the journal homepage: https://academic.oup.com/pcm