22:T4f3,Limited therapeutic efficacy to hypoxic and refractory solid tumors has hindered the practical application of photodynamic therapy (PDT). Two new benzothiophenylisoquinoline (btiq)-derived cyclometalated Ir^III complexes, IrL1 and MitoIrL2, were constructed as potent photosensitizers, with the latter being designed for mitochondria accumulation. Both complexes demonstrated a type I PDT process and caused photoinduced ferroptosis in tumor cells under hypoxia. This ferroptosis featured lipid peroxide accumulation, mitochondria shrinkage, down-regulation of glutathione peroxidase 4 (GPX4), and ferrostatin-1 (Fer-1)-inhibited cell death. Upon photoirradiation under hypoxia, mitochondria targeting MitoIrL2 caused mitochondria membrane potential (MMP) collapse, ATP production suppression, and induced cell apoptosis. The synergetic effect of ferroptosis and apoptosis causes MitoIrL2 to outperform IrL1 in inhibiting the growth of MCF-7, PANC-1, MDA-MB-231 cells and multicellular spheroids. This study demonstrates the first example of ferroptosis induced by photosensitizing Ir^III complexes. Moreover, the synergism of ferroptosis and apoptosis provides a promising approach for combating hypoxic solid tumors through type I PDT processes.23:T498,Tumor hypoxia seriously impairs the therapeutic outcomes of type II photodynamic therapy (PDT), which is highly dependent upon tissue oxygen concentration. Herein, a facile strategy of acceptor planarization and donor rotation is proposed to design type I photosensitizers (PSs) and photothermal reagents. Acceptor planarization can not only enforce intramolecular charge transfer to redshift NIR absorption but also transfer the type of PSs from type II to type I photochemical pathways. Donor rotation optimizes photothermal conversion efficiency (PCE). Accordingly, three 3,6-divinyl-substituted diketopyrrolopyrrole (DPP) derivatives, 2TPAVDPP, TPATPEVDPP, and 2TPEVDPP, with different number of rotors were prepared. Experimental results showed that three compounds were excellent type I PSs, and the corresponding 2TPEVDPP nanoparticles (NPs) with the most rotors possessed the highest PCE. The photophysical properties of 2TPEVDPP NPs are particularly suitable for in vivo NIR fluorescence imaging-guided synergistic PDT/PTT therapy. The proposed strategy is helpful for exploiting type I phototherapeutic reagents with high efficacy for synergistic PDT and PTT.24:T4cb,Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (¹O₂). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors.

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