A Versatile Tumor Microenvironment-Responsive Nanoprobe for Cancer Screening and Early Detection

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Abstract
It has been highly challenging to reliably detect various cancers at an early stage when tumors are just millimeters in size. To address this, we developed a tumor microenvironment (TME)-responsive nanoprobe, PR-KAd@CD-AuNC, enabling cross-validated cancer detection through in vivo second near-infrared (NIR-II) fluorescence imaging and in vitro colorimetric urinalysis. The nanoprobe consists of three integrated components: a renal-clearable signal-output segment (cyclodextrin-functionalized gold nanocluster, CD-AuNC), a tumor-targeting and size-controlling component (PR), and a matrix metalloproteinase-2 (MMP2)-cleavable linker (KAd). PR, composed of 8-arm poly(ethylene glycol) for prolonged circulation and c(RGDfK) peptides for αvβ3 integrin targeting, directed selective tumor accumulation after intravenous injection of PR-KAd@CD-AuNC. The intrinsic emission of CD-AuNC above 1100 nm enabled high-resolution, real-time NIR-II fluorescence imaging with attenuated photon scattering, allowing precise tumor delineation. Within the TME, specifically overexpressed MMP2 cleaved the KAd linker, releasing ∼2 nm CD-AuNC fragments from the ∼10 nm parent nanoprobe. Being smaller than the ∼5.5 nm renal filtration threshold, these fragments were renally excreted. Concurrently, the peroxidase-like activity of CD-AuNC catalyzed tetramethylbenzidine oxidation to produce a visible blue signal, providing a simple and low-cost urinalysis method suitable for broad cancer screening applications. This dual-modality strategy effectively distinguished cancers from inflammation and other diseases, detecting small tumors for multiple cancer types with a sensitivity surpassing that of computed tomography (CT) imaging, which makes it a promising early detection approach. Furthermore, it was also employed to dynamically assess cancer therapeutic efficacy (i.e., immunotherapy, chemotherapy, and surgical resection), suggesting clinical value for guiding treatment decisions.
Funding Information
  • Natural Science Foundation of Jiangxi Province (20224ACB215009)
  • Natural Science Foundation of Jiangxi Province (20232ACB205024)
  • JC STEM Lab of Nanoscience and Nanomedicine, General Research Fund (17212424)
  • National Natural Science Foundation of China (32101212)
  • National Natural Science Foundation of China (32372322)
  • Central Guidance Fund for Local Science and Technology Development in Jiangxi Province (20252ZDD020002)

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