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Signal amplification strategies are essential for sensitive and efficient detection. Among the recent amplification strategies, the hybridization chain reaction has been intensively studied because it has advantages of reaction at constant temperature and detection at low cost without specialized equipment. In this review, we have discussed how to adjust experimental conditions of the hybridization chain reaction and attractive signal amplification techniques including colorimetric, fluorescence, and electrochemistry. As a result, many studies using the hybridization chain reaction have been successful in detecting sensitive signals by enhancing the signaling of the various targets. These exciting features of the hybridization chain reaction have the potential to be widely used in many areas such as in situ disease diagnosis, food, and environmental analysis. Therefore, various platforms developed by applying this technology are expected to play an essential role as an efficient biosensor in many fields in the near future.

On-site genetic detection needs to develop a sensitive and straightforward biosensor without special equipment, which can detect various genetic biomarkers. Hybridization chain reaction (HCR) amplifying signal isothermally could be considered as a good candidate for on-site detection. Here, we developed a novel genetic biosensor on the basis of enzyme-free dual-amplification of universal hybridization chain reaction (uHCR) and hemin/G-quadruplex horseradish peroxidase (HRP)-mimicking DNAzyme. The uHCR is the strategy which enables simple design for multiple target detection by the introduction of target-specific trigger hairpin without changing the whole system according to a target change. Also, HRP-mimicking DNAzyme could produce a sensitive and quantitative colorimetric signal with increased stability with a limit of detection (LOD) of 5.67 nM. The universality of the uHCR biosensor was proven by the detection of four different targets (miR-21, miR-125b, KRAS-Q61K, and BRAF-V600E) for cancer diagnosis. The uHCR biosensor showed specificity that could discriminate single-nucleotide polymorphism. Moreover, the uHCR biosensor could detect targets in the diluted serum sample. Overall, the uHCR biosensor demonstrated the potential for field testing with a simple redesign without complicated steps or special equipment using a universal hairpin system and enzyme-free amplification. This strategy could enable stable and sensitive detection of a variety of targets. Therefore, it could be applied to urgent detection of various pathogens, remote diagnosis, and self-screening of diseases.