Microenvironment-Driven Cascaded Responsive Hybrid Carbon Dots as a Multifunctional Theranostic Nanoplatform for Imaging-Traceable Gene Precise Delivery

Imaging-guided stimuli-responsive delivery systems based on nanomaterials for cancer theranostics have been recognized as promising alternatives to traditional therapies in clinic. How to integrate multiple response-mediated nanoproperty (i.e., charge, size, or stability) transitions into a cascaded manner to overcome multistage biological barriers which usually demand different and even opposing nanoproperties in each stage is still a challenge. Herein, a multistage and cascaded responsive theranostic nanoplatform for imaging-traceable TRAIL gene precise delivery was prepared by a cleavable PEGylated shell and a fluorescent carbon dot (CD)-based core. The CDs as the core were prefunctionalized with polyethylenimine end-capped disulfide-bond-bearing hyperbranched poly(amido amine) (HPAP), endowing the CDs with enhanced fluorescent quantum yield (27%), intracellular degradability, and efficient gene delivery capability. The shell was fabricated by dimethylmaleic acid modification of mPEG-PEI600 copolymer and exhibited tumor microenvironment-triggered charge reversal, leading to the shell detachment from the core at the tumor site. The nanoplatform with cascaded responsive property displays prolonged blood circulation time benefiting from PEGylated shielding once being injected into blood, subsequently effective accumulation at tumor tissues from blood induced by the elevated EPR effect resulting from the microenvironment-driven synchronous charge conversion and size shrinkage, and finally controlled gene release in tumor cell cytosol facilitated by glutathione-triggered HPAP degradability. In vitro and in vivo assays demonstrated that such a blood–tissue–cell cascaded responsive nanoplatform not only possessed imaging-trackable tumor-specific delivery ability but also exhibited enhanced and selective antitumor activity through TRAIL-mediated apoptosis as well as excellent biocompatibility. This study provides a multifunctional integration strategy, paving the way for designing novel theranostic nanomedicines on the basis of precision medicine.