Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
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K.P. thanks the Ministry of Education Singapore, Academic Research Fund Tier 1 (2019-T1-002-045 RG125/19 and RT05/20) and Academic Research Fund Tier 2 (MOE2018-T2-2-042 and MOE-T2EP30220-0010) for financial support. H.W. thanks the Zhejiang Provincial Natural Science Foundation of China (LR19H160002) and the National Natural Science Foundation of China (82073296 and 81773193) for financial support.
The authors declare no competing interests.
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Data for spectrum, selectivity studies, HPLC spectrum and so on.
Data for NIRF intensity in liver and kidney, residual probes in livers and blood, clearance efficiencies and so on.
Data for NIRF intensity in urine, liver and kidneys, data for liver and kidney function tests and so on.
Data for NIRF intensity of liver and kidneys, signal enhancement in urine, flow cytometry and cytokines and so on.
Data for NIRF intensity in urine, liver and kidneys, data for ROC curves and so on.
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Huang, J., Chen, X., Jiang, Y. et al. Renal clearable polyfluorophore nanosensors for early diagnosis of cancer and allograft rejection. Nat. Mater. 21, 598–607 (2022). https://doi.org/10.1038/s41563-022-01224-2