Carbon Nitride Hollow Theranostic Nanoregulators Executing Laser-Activatable Water Splitting for Enhanced Ultrasound/Fluorescence Imaging and Cooperative Phototherapy

The limited efficacy of "smart" nanotheranostic agents in eradicating tumors calls for the development of highly desirable nanoagents with diagnostics and therapeutics. Herein, to surmount these challenges, we constructed an intelligent nanoregulator by coating a mesoporous carbon nitride (C3N4) layer on a core-shell nitrogen-doped graphene quantum dot (N-GQD)@hollow mesoporous silica nanosphere (HMSN) and decorated it with a P-PEG-RGD polymer, to achieve active-targeting delivery (designated as R-NCNP). Upon irradiation, the resultant R-NCNP nanoregulators exhibit significant catalytic breakdown of water molecules, causing a sustainable elevation of oxygen level owing to the C3N4 shell, which facilitates tumor oxygenation and relieves tumor hypoxia. The generated oxygen bubbles serve as an echogenic source, triggering tissue impedance mismatch, thereby enhancing the generation of an echogenicity signal, making them laser-activatable ultrasound imaging agents. In addition, the encapsulated photosensitizers and C3N4-layered photosensitizer are simultaneously activated to maximize the yield of ROS, actualizing a triple-photosensitizer hybrid nanosystem exploited for enhanced PDT. Intriguingly, the N-GQDs endow the R-NCNP nanoregulator with a photothermal effect for hyperthemia, making it exhibit considerable photothermal outcomes and infrared thermal imaging (IRT). Importantly, further analysis reveals that the polymer-modified R-NCNPs actively target specific tumor tissues and display a triple-modal US/IRT/FL imaging-assisted cooperative PTT/PDT for real-time monitoring of tumor ablation and therapeutic evaluation. The rational synergy of triple-model PDT and efficient PTT in the designed nanoregulator confers excellent anticancer effects, as evidenced by in vitro and in vivo assays, which might explore more possibilities in personalized cancer treatment.