Synthesis and Application\nof a Novel Multifunctional\nNanoprodrug for Synergistic Chemotherapy and Phototherapy with Hydrogen\nSulfide Gas

With\nthe dilemma of limited efficacy of individual therapies, it\nis crucial to develop innovative combination therapy systems to target\nthe complex pathogenesis of cancer. In this study, we designed a nanoprodrug\nISL@MIL-101-ADT to facilitate synergistic delivery of hydrogen sulfide\n(H<sub>2</sub>S) and prodrug ISL for specific eradication of tumor\ncells with minimal toxicity and maximal efficacy. The nanoprodrug\npassively targeted tumors through enhanced permeation and retention\neffects, followed by disintegration and release of IR780, lonidamine\n(LND), and H<sub>2</sub>S. IR780 localizes LND to mitochondria to\nenhance therapeutic effects and turn on the phototherapy and chemotherapy\nwhen exposed to a laser; H<sub>2</sub>S inhibits procancer signaling\npathways and mitochondrial function. In vivo experiments have demonstrated\nthat ISL@MIL-101-ADT exhibits excellent pharmacokinetic properties\nand significant tumor inhibitory effects. Additionally, this nanoprodrug\npossesses outstanding photothermal and fluorescence imaging capabilities.\nTherefore, we strongly believe that the nanoprodrug present herein\nholds great potential for application in cancer therapy.