Cathepsin B-induced cascade DNA-AuNP nanomachine for activated tumor theranostics

Since targeted and efficient accumulation of nanoparticles into tumors is essential for accurate cancer theranostics, spatiotemporally controlling the aggregation of small nanoparticles (such as gold nanoparticles, AuNPs) in the tumor microenvironment holds significant promise for improving the diagnostic and therapeutic efficiency against tumors. Here, we introduce a cascade DNA-AuNP nanomachine (CNM) that can in situ magnify the protease-catalyzed peptide cleavage via DNA amplification machinery for cathepsin B (Cat B) activity imaging and Cat B-responsive photothermal therapy of tumors. The CNM is composed of a nanomediator formed by tethering a mediator DNA/peptide complex on AuNPs (DpAuNP) and a nanoeffector consisted of AuNPs and DNA modules (DNA-AuNP). In the cascade, Cat B-mediated peptide cleavage of mediator DNA/peptide complex on DpAuNPs initiates both the detachment of fluorescent DNA reporter from DNA-AuNPs for Cat B imaging and the aggregation of AuNPs for tumor photothermal therapy via toehold-mediated stand displacement (TMSD) reaction. Our results demonstrate that the CNM not only offers superior sensitivity and specificity for Cat B imaging, but also facilitates the activated aggregation of AuNPs for enhanced photothermal therapy of tumors. This CNM represents a Cat B-specific sense-and-treat paradigm for cancer theranostics.