Limited therapeutic efficacy to hypoxic and refractory solid tumors has hindered the practical application of photodynamic therapy(PDT). Tw on ew benzothiophenylisoquinoline (btiq)-derived cyclometalated Ir III complexes, IrL1 and MitoIrL2,w ere constructed as potent photosensitizers, with the latter being designed for mitochondria accumulation. Both complexes demonstrated at ype IP DT process and caused photoinduced ferroptosis in tumor cells under hypoxia. This ferroptosis featured lipid peroxide accumulation, mitochondria shrinkage,d own-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,A TP production suppression, and induced cell apoptosis.T he 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.T his study demonstrates the first example of ferroptosis induced by photosensitizing Ir III complexes.Moreover,t he synergism of ferroptosis and apoptosis provides ap romising approach for combating hypoxics olid tumors through type IP DT processes.

Mitochondria–lysosome interactions are essential for maintaining intracellular homeostasis. Although various fluorescent probes have been developed to visualize such interactions, they remain unable to label mitochondria and lysosomes simultaneously and dynamically track their interaction. Here, we introduce a cell-permeable, biocompatible, viscosity-responsive, small organic molecular probe, Coupa, to monitor the interaction of mitochondria and lysosomes in living cells. Through a functional fluorescence conversion, Coupa can simultaneously label mitochondria with blue fluorescence and lysosomes with red fluorescence, and the correlation between the red–blue fluorescence intensity indicates the progress of mitochondria–lysosome interplay during mitophagy. Moreover, because its fluorescence is sensitive to viscosity, Coupa allowed us to precisely localize sites of mitochondria–lysosome contact and reveal increases in local viscosity on mitochondria associated with mitochondria–lysosome contact. Thus, our probe represents an attractive tool for the localization and dynamic tracking of functional mitochondria–lysosome interactions in living cells.

A photosensitizing monofunctional Pt complex, Pt‐BDPA, was prepared with a BODIPY chromophore. Apart from its DNA binding ability, this complex displays emission at ca. 578 nm and a singlet oxygen quantum yield of 0.133. Confocal imaging revealed that this complex was sequestered in lysosomes via endocytosis in the dark, preventing its access to the nucleus. Profiting from its photoinduced ROS generation ability, this complex undergoes lysosomal escape to access the nucleus upon photoirradiation. The photoinduced ROS still cause a drop in intracellular GSH, favoring the stability of Pt‐BDPA and contributing to its nuclear DNA accessibility. This complex displayed distinct cytotoxicity to all tested tumor cell lines upon photoirradiation, and the IC50 values were ca. 3–6 μm, which are distinctly lower than those found with only dark incubation (IC50>50 μm). These results are consistent with photoactivated lysosomal escape of this photosensitizing Pt complex to access the nucleus.

As the cleaners of cells, lysosomes play an important role in circulating organic matter within cells, recovering damaged organelles, and removing waste via endocytosis. Because lysosome dysfunction is associated with various diseaseslysosomal storage diseases, inherited diseases, rheumatoid arthritis, and even shockit is vital to monitor the movement of lysosomes in cells and in vivo. To that purpose, a method of optical imaging, super-resolution imaging technology (e.g., SIM and STORM), can overcome the limitations of traditional optical imaging and afford a range of possibilities for fluorescence imaging. However, the short wavelength excitation and easy photobleaching of super-resolution fluorescence probes somewhat problematize super-resolution imaging. As described herein, we designed a low-toxicity, photostable, near-infrared small molecule fluorescence probe HD-Br for use in the super-resolution imaging of lysosomes. The interaction of lysosomes and mitochondria was dynamically traced while using the probe’s properties to label the lysosomes. Because the probe has the optimal near-infrared excitation and emission wavelengths, liver organoid 3D imaging and Caenorhabditis elegans imaging were also performed. Altogether, our findings indicate valuable approaches and techniques for super-resolution 3D and in vivo imaging.