Abstract
Circular RNAs (circRNAs), a unique class of non-coding RNAs, have gained attention due to their stable closed-loop structure and involvement in diverse cellular processes. Their remarkable stability and abundance in biological fluids, particularly when encapsulated within exosomes, make them highly promising candidates for clinical applications. This review offers a detailed insight into the growing field of exosomal circRNAs, starting with the fundamental principles of circRNA biogenesis and the selective mechanisms governing their sorting into exosomes. We explore the complex regulatory network controlled by circRNAs, highlighting their roles as microRNA (miRNA) sponges, interactors with RNA-binding proteins (RBPs), regulators of transcription and RNA stability, and even as templates for translating into novel peptides or proteins. We elucidate how these actions are mediated by exosomal circRNAs when delivered to recipient cells, influencing the behavior of target cells. The review critically evaluates the current and emerging methodologies for the detection, quantification, and functional analysis of exosomal circRNAs. We extensively discuss the clinical implications, highlighting the significant potential of exosomal circRNAs as non-invasive biomarkers for the diagnosis, prognosis, and monitoring of various diseases, with a particular focus on cancer. Furthermore, we explore their therapeutic landscape, including strategies for targeted delivery, their role in modulating drug resistance, and their intricate functional crosstalk with other non-coding RNAs in cancer progression. While recognizing the promising potential of exosomal circRNAs, we also address the existing technical challenges and highlight the future directions needed to leverage their diagnostic and therapeutic applications. Our review highlights the significance of interpreting the circular code of exosomal circRNAs as a vital step toward achieving the objectives of precision medicine. GRAPHICAL ABSTRACT: [Image: see text]