Nitrile-aminothiol bioorthogonal near-infrared fluorogenic probes for ultrasensitive in vivo imaging

Weiping Xu, Shujuan Yi, Jie Liu, Yuyan Jiang and Jiaguo Huang (huangjg36@mail.sysu.edu.cn)
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Weiping Xu: Sun Yat-sen University
Shujuan Yi: Sun Yat-sen University
Jie Liu: University of Chinese Academy of Sciences
Yuyan Jiang: Stanford University School of Medicine
Jiaguo Huang: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Bioorthogonal chemistry-mediated self-assembly holds great promise for dynamic molecular imaging in living organisms. However, existing approaches are limited to nanoaggregates with ‘always-on’ signals, suffering from high signal-to-background ratio (SBR) and compromised detection sensitivity. Herein we report a nitrile-aminothiol (NAT) bioorthogonal fluorogenic probe (CyNAP-SS-FK) for ultrasensitive diagnosis of orthotopic hepatocellular carcinoma. This probe comprises a nitrile-substituted hemicyanine scaffold with a cysteine tail dually locked with biomarker-responsive moieties. Upon dual cleavage by tumor-specific cathepsin B and biothiols, the 1,2-aminothiol residue is exposed and spontaneously reacts with nitrile group for in situ intramolecular macrocyclization, enabling near-infrared fluorescence (NIRF) turn-on as well as self-assembly. In living male mice, such ‘cleavage-click-assembly’ regimen allows for real-time and ultrasensitive detection of small cancerous lesions (~2 mm in diameter) with improved SBR (~5) and extended detection window (~36 h), outperforming conventional clinical assays. This study not only presents NAT click reaction-based fluorogenic probes but also highlights a generic dual-locked design of these probes.

Date: 2025
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DOI: 10.1038/s41467-024-55452-y

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