Passive and active biosensing with nucleic acid-protein hybrid nanostructures

Advanced profiling of multiple biomarkers can individualize patient characterization and empower precision medicine. Conventional diagnostic methods, however, often require extensive processing and lack assay versatility and/or multiplexing capacity to accommodate different biomarkers. To address these challenges, nucleic acid-protein hybrid nanostructures have emerged as a promising technology. These hybrids offer multifaceted versatility. On the component level, they benefit from the inherent structural programmability of nucleic acids and the functional versatility of proteins to accommodate diverse biomarkers; as integrated assemblies, they can operate as passive labeling constructs or active enzymatic machines to meet varying diagnostic needs. In this review, we highlight recent synergistic advances in the molecular configuration and mechanism design of these hybrid systems to measure a broad spectrum of biomarkers, ranging from classical nucleic acid and protein biomarkers to novel modifications and interactions. Finally, we provide an outlook on emerging trends in biomarker discovery and technology development that position nucleic acid-protein hybrids as powerful tools for precision diagnostics.