PR-KAd@CD-AuNC nanoprobe enables dual-modality early cancer detection via NIR-II imaging and urinalysis

Reliably detecting diverse cancers at early stages, when tumors are only millimeters in size, remains a significant challenge. Current imaging modalities often lack the sensitivity or specificity required for such minute lesions, leading to delayed diagnoses and poorer prognoses. There is a critical need for versatile, non-invasive, and highly sensitive methods that can distinguish early-stage cancers from inflammation or other benign conditions. Leveraging the unique biochemical characteristics of the tumor microenvironment (TME), such as overexpression of specific enzymes like matrix metalloproteinase-2 (MMP2), offers a promising avenue for targeted and responsive diagnostic tools.

Researchers engineered a tumor microenvironment (TME)-responsive nanoprobe, PR-KAd@CD-AuNC, for dual-modality cancer detection. The nanoprobe comprises three integrated components: a renal-clearable signal-output segment (CD-AuNC, cyclodextrin-functionalized gold nanocluster), a tumor-targeting and size-controlling component (PR, 8-arm poly(ethylene glycol) conjugated with c(RGDfK) peptides for αvβ3 integrin targeting), and an MMP2-cleavable linker (KAd). The PR-KAd@CD-AuNC nanoprobe was administered intravenously. Cancer detection was performed via in vivo second near-infrared (NIR-II) fluorescence imaging and in vitro colorimetric urinalysis (catalyzed tetramethylbenzidine oxidation).

The PR-KAd@CD-AuNC nanoprobe, initially ~10 nm in size, demonstrated selective tumor accumulation due to its c(RGDfK) peptides targeting αvβ3 integrin. Within the TME, specifically overexpressed MMP2 cleaved the KAd linker, releasing ~2 nm CD-AuNC fragments. These fragments, being smaller than the ~5.5 nm renal filtration threshold, were efficiently renally excreted. 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. Concurrently, the peroxidase-like activity of CD-AuNC catalyzed tetramethylbenzidine oxidation, producing a visible blue signal in urine. This dual-modality strategy effectively distinguished cancers from inflammation and other diseases. > The nanoprobe detected small tumors for multiple cancer types with a sensitivity surpassing that of computed tomography (CT) imaging. Furthermore, it was successfully employed to dynamically assess cancer therapeutic efficacy, including immunotherapy, chemotherapy, and surgical resection.