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Nucleic acids have become viable prognostic and diagnostic biomarkers for a diverse class of diseases, particularly cancer. However, the low femtomolar to attomolar concentration of nucleic acids in human samples require sensors with excellent detection capabilities; many past and current platforms fall short or are economically difficult. Strand-mediated signal amplifiers such as hybridization chain reaction (HCR) and catalytic hairpin assembly (CHA) are superior methods for detecting trace amounts of biomolecules because one target molecule triggers the continuous production of synthetic double-helical DNA. This cascade event is highly discriminatory to the target via sequence specificity, and it can be coupled with fluorescence, electrochemistry, magnetic moment, and electrochemiluminescence for signal reporting. Here, we review recent advances in enhancing the sensing abilities in HCR and CHA for improved live-cell imaging efficiency, lowered limit of detection, and optimized multiplexity. We further outline the potential for clinical translatability of HCR and CHA by summarizing progress in employing these two tools for in vivo imaging, human sample testing, and sensing-treating dualities. We finally discuss their future prospects and suggest clinically-relevant experiments to supplement further related research.

Hybridizing clinical translatability with enzyme-free DNA signal amplifiers: recent advances in nucleic acid detection and imaging