Smart MMP2-Responsive Nanoprobe for Activatable Fluorescence Imaging-Guided Local Triple-Combination Therapies with...

Elaborately designed stimuli-responsive smart systems simultaneously enabling activatable imaging and selective treatment are highly desirable for precise diagnosis and therapy of cancer. Herein, such a smart theranostic nanoprobe composed of hollow gold nanospheres (HAuNs), photosensitizer (PS), matrix metalloproteinase 2 (MMP2) substrate peptide, and model drug doxorubicin (DOX) was designed. In the design, HAuNs served as the acceptor of Förster resonance energy transfer (FRET), photothermal therapy (PTT) reagent, and nanocarrier. The fluorescence and ¹O₂ generation of PS were inhibited by HAuNs through FRET effect, avoiding phototoxicity to normal tissues during circulation. Meanwhile, owing to the MMP2-triggered peptide cleavage, the PS could be efficiently activated in a tumor for selective fluorescence imaging and photodynamic therapy (PDT). The recovered fluorescence could be applied for detecting MMP2, locating tumor in vivo, and further guiding the local triple-combination therapies including PDT, PTT, and chemotherapy. The synergistic treatments of activated PDT, PTT, and controlled DOX release were achieved with single light, which provided the best therapeutic effects with enhanced stability and remarkably reduced nonspecific toxicity of PS and anticancer drug. This study helps to design novel stimuli-responsive systems for precise molecular sensing and site-specific cancer treatment.