Silent-To-Bright CTCs-Hitchhiking Peptide Nanoprobe for Activatable NIR Imaging of Lung Metastasis in Mice.

Metastasis remains the leading cause of cancer-related mortality, yet its early detection is hindered by the subtle and unpredictable nature of the metastatic niche. In this study, we developed a self-assembling peptide-based activatable nanoprobe, 1-CyBr(PBA)-NGR NPs, designed for the early detection of the metastatic niche through circulating tumor cells (CTCs)-mediated hitchhiking and hydrogen peroxide (H2O2)-induced fluorescence activation. The peptide probe spontaneously assembled into stable spherical nanoparticles in aqueous media and undergoes H2O2-triggered fluorescence recovery via oxidation of the phenylboronic acid masking group. Upon intravenous injection, 1-CyBr(PBA)-NGR NPs "hitchhike" CTCs through specific binding via the NGR moiety, utilizing the natural trafficking pathways of CTCs to reach the metastatic lesion. Upon reaching the metastatic site, the nanoparticles are selectively activated by the microenvironment, resulting in fluorescence activation and enabling precise optical imaging of the metastatic site. In vivo imaging in a lung metastatic mouse model revealed distinct fluorescence in the lungs following intravenous administration of 1-CyBr(PBA)-NGR NPs, whereas minimal fluorescence was observed in both the healthy control and antioxidant N-acetylcysteine (NAC)-treated metastatic mice, further confirming the probe's selective activation in response to the elevated H2O2 levels in the metastatic lesion. This study presents a "silent-to-bright" NIR imaging strategy for tumor metastasis monitoring, utilizing CTCs as "hitchhiking" carriers and the metastatic microenvironment as fluorescence activators, offering a promising approach for tumor metastasis diagnosis and intervention.