Abstract

Mitochondria-targeted photodynamic therapy (PDT) represents an attractive therapeutic strategy for antitumor therapy. There is growing evidence indicating that in situ generation of reactive oxygen species (ROS) in mitochondria plays a critical role in significant mitochondrial dysfunction and cell apoptosis. Nevertheless, survivin, a member of the inhibitor of apoptosis protein (IAP) family, is overexpressed by PDT stimulation, which inhibit cysteine aspartic acid specific protease-9 (caspase-9) activation and inhibits apoptosis. The corresponding overexpression of Livin protein in tumor cells can inhibit cysteine aspartic acid specific protease-3 (caspase-3) activity, leading to apoptosis inhibition and promoting tumorigenesis and tumor progression. Thus, a precise combination of mitochondria-targeted photodynamic photosensitizers and IAP inhibitor is expected to significantly augment the PDT efficacy. For proof-of-concept, a therapeutic nanoplatform MSNs/GM/I3C-BSA/MnO 2 -IR775 (MGIBR) was ingeniously constructed for synergistic cancer therapy. MGIBR can effectively target mitochondria due to the presence of IR775. Under NIR irradiation, MGIBR can generate in situ 1 O 2 in mitochondria. Importantly, geldanamycin (GM) and indole-3-carbinol (I3C) can inhibit IAP, synergistic enhance PDT and activate mitochondrial apoptosis pathways, leading to effectively cell death. Such a strategy of MGIBR enabled mitochondrial dysfunction based on in situ generation of ROS in mitochondria and IAP inhibitor synergistically, provides a promising paradigm for highly effective cancer therapeutics.