Supramolecular Nanoparticles Based on Galactose Functionalized Pillar[5]arene for Synergistic Photothermal/Photodynamic/CO Gas Multimodal Cancer Therapy

Abstract Gas therapy based on carbon monoxide (CO) is an emerging anticancer strategy. However, conventional CO donors suffer from uncontrolled gas release and poor therapeutic efficacy. Developing a multimodal therapeutic system combining CO gas therapy and phototherapy modalities, which is of great significance for improving the efficacy of tumor treatment. Herein, a supramolecular nanoparticle loaded with BODIPY photosensitizer (BOD-GP5⊃HFMI) was developed by host−guest self-assembly of galactosylated pillar[5]arene (GP5) and 3-hydroxyflavone derivative (HFMI). Galactose modification enhanced cellular uptake in B16F10 melanoma cells via glucose transporter-1-mediated recognition. Upon NIR irradiation (685 nm), the generated ROS trigger the degradation of the benzene ring structure of HFMI to release HFMI and BODIPY. The released BODIPY converted NIR light energy into thermal energy and the generated ROS, where the generated ROS trigger HFMI to release CO gas, thereby achieving a spatiotemporally controlled photodynamic/photothermal/CO gas multimodal synergistic cancer therapy. Notably, the released CO could cyclically amplify intracellular ROS levels via mitochondrial dysfunction. Studies in vitro and in vivo exhibited that BOD-GP5⊃HFMI achieved an enhanced cancer therapeutic effect without obvious systemic toxicity. This NIR light-triggered, cyclic-amplifying strategy provides a new paradigm for synergistically enhanced cancer therapeutic effectiveness.