Advancing precision medicine with bioelectroanalytical technologies leveraging unconventional nucleic acid forms

The non-canonicity at the DNA and RNA levels that characterizes the intriguing world of nucleic acids is redefining our understanding of gene regulation, cellular responses, and the mechanisms that orchestrate the emergence, onset, and evolution of diseases. These atypical, mysterious, and Watson-Crick deviating DNA and RNA structural configurations include circular RNAs (circRNAs), transfer RNA-derived fragments (tRFs), G-quadruplexes (G4s), and related biotargets, such as telomerase, and are increasingly recognized as pivotal biomarkers and functional targets in precision and personalized medicine, particularly for the moment, in the neurodegenerative and oncological landscapes. Their structural uniqueness and disease-specific expression patterns and profiles position them as ideal candidates for the early diagnosis and tailored therapies. In turn, electrochemical biosensing, despite guaranteeing high sensitivity, low cost, and suitability for point-of-care applications, represents a powerful yet underutilized tool for detecting these complex promising molecular entities. Strikingly, and to the best of our knowledge, there is currently no dedicated vision addressing this important issue. Therefore, with the aim of contributing to bridge this void, this review compiles the latest efforts recently made for unlocking the diagnostic and therapeutic potentials of these enigmatic and naturally occurring biostructures and their most relevant related biotargets through the employment of bioelectroanalytical technologies.