Engineering of ATP-Powered Photosensitizer for Targeted Recycling Activatable Imaging of MicroRNA and Controllable Cascade Amplification Photodynamic Therapy.

Abstract

Owing to the low abundance of microRNAs (miRNAs) in living tumor cells, the development of intracellular cancer-relevant miRNA stimuli-activatable photosensitizers (PSs) for accurate imaging and efficient photodynamic therapy (PDT) of tumors in vivo is extremely challenging. Herein, we engineered a tumor targeting and intracellular trace miRNA-activatable nanophotosensitizer Y-motif/FA@HyNP on the basis of an endogenous ATP-powered strand-displacement cascade amplification strategy, which was prepared by assembly of a quencher BHQ2-labeled Y-motif DNA structure (containing ATP-binding aptamer and target miRNA-binding complementary sequence) on the surface of folate (FA) and amine-functionalized hybrid micellar nanoparticles. We showed that the fluorescence emissions at both 555 and 627 nm were effectively inhibited due to BHQ2 in Y-motif/FA@HyNPs, leading to negligible PDT efficacy. Once Y-motif/FA@HyNPs were selectively internalized into tumor cells via FA-receptor-mediated endocytosis, the intracellular trace target miRNA initiated the dissociation of the BHQ2-terminated sequences from Y-motif/FA@HyNPs by means of abundant endogenous ATP-powered strand-displacement reactions, causing remarkable fluorescence enhancement and cascade amplification PDT. The activated dual-color fluorescence emissions at 555 and 627 nm were feasible to achieve real-time, highly sensitive, and specific imaging of trace target miRNA in living tumor cells. With the guidance of excellent imaging in living mice, Y-motif/FA@HyNPs exhibited the precise and efficient PDT of tumors as well as insignificant side effects in vivo. This work revealed the great potential of using an integration of receptor-mediated cell uptake and target-triggered recycling cascade amplification strategy to design early cancer-relevant stimuli-activatable PSs for both fluorescence imaging and PDT ablation of tumors in vivo, which could effectively facilitate the timeliness and precision of early cancer diagnosis and therapy.