Smart Nucleic Acid Hydrogel-Based Biosensors: From Molecular Recognition and Responsive Mechanisms to Applications

Smart nucleic acid hydrogels (SNAHs), endowed with stimulus responsiveness, function as programmable molecular switches that can perceive diverse external stimuli and undergo rapid, reversible, and highly specific conformational or performance changes. These dynamic properties have enabled the rational design of biosensors with bionic behaviors, facilitating cascaded "recognition-decision-execution" processes that support advanced biological analysis. Consequently, SNAHs are recognized as a core breakthrough for the next generation of intelligent biosensing units. However, a systematic mapping between SNAH design strategies, specific stimuli, and application fields remains lacking. This review mainly analyzes advances in SNAH-based biosensors over the past five years, proposing flexible and feasible design strategies and key trends in customization. Firstly, we systematically summarize molecular recognition modules involved in the construction of SNAHs, including aptamers, DNAzymes, antibodies, and specific binding peptides. Subsequently, we elaborate on the responses of these modules to external stimuli, so as to further facilitate the signal transduction of signals derived from physical, chemical, and biological sources involving temperature, light, magnetic fields, pH, nucleic acids, proteins, other biomolecules, and pathogens. Additionally, the review outlines the research progress of SNAHs in environmental monitoring, food safety, and medical diagnostics. Finally, we provide an integrated perspective on future opportunities and challenges, highlighting the innovative framework for designing SNAH-based biosensors and offering a practical roadmap for next-generation intelligent sensing applications.