Epilepsy is a chronic neurodegenerative disease, and accumulating evidence suggests its pathological progression is closely associated with peroxynitrite (ONOO − ). However, understanding the function remains challenging due to a lack of in vivo imaging probes for ONOO − determination in epileptic brains. Here, the first near‐infrared imaging probe (named ONP) is presented for tracking endogenous ONOO − in brains of kainate‐induced epileptic seizures with high sensitivity and selectivity. Using this probe, the dynamic changes of endogenous ONOO − fluxes in epileptic brains are effectively monitored with excellent temporal and spatial resolution. In vivo visualization and in situ imaging of hippocampal regions clearly reveal that a higher concentration of ONOO − in the epileptic brains associates with severe neuronal damage and epileptogenesis; curcumin administration can eliminate excessively increased ONOO − , further effectively protecting neuronal cells. Moreover, by combining high‐content analysis and ONP, a high‐throughput screening method for antiepileptic inhibitors is constructed, which provides a rapid imaging/screening approach for understanding epilepsy pathology and accelerating antiseizure therapeutic discovery.

Non-small cell lung cancer (NSCLC) is a primary threat to human health. Cisplatin is always in first-line treatment of NSCLC; however, cisplatin resistance restricts the application in the clinic. Herein, an innovative 2D platinum delivery platform based on manganese dioxide nanosheet is presented to overcome cisplatin-resistance and enhance theranostic efficacy in NSCLC. The photo-induced hyperthermia of nanosheets can inhibit Pt drug efflux from the multidrug resistance-associated protein (MRP1) repression. Then the intracellular l-Glutathione (GSH) consumed by MnO 2 nanosheets can reduce the generation of GSH-Pt complex. Working along both lines accelerates access to the nucleus for cisplatin. Moreover, chemophotothermal synergistic therapy of Pt nanosheets significantly enhances therapeutic efficacy in vitro and in vivo. In addition, nanosheets can exert an on-demand activable magnetic resonance imaging contrast effect to monitor Pt drug release. For the first time, a promising photoactivated 2D vector is provided to overcome cisplatin resistance in NSCLC therapy.

Sensitizing the antitumor activity of monofunctional Pt complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional Pt complexes, in this study, the photosensitizing monofunctional Pt complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the Pt center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional Pt complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional Pt complex and renders the possibility of monofunctional Pt prodrugs for precise chemotherapy via only short time photoactivation.

Metabolic adaptations can help cancer cells to escape from chemotherapeutics, mainly involving autophagy and ATP production. Herein, we report a new rhein‐based cyclometalated IrIII complex, Ir‐Rhein, that can accurately target mitochondria and effectively inhibit metabolic adaptations. The complex Ir‐Rhein induces severe mitochondrial damage and initiates mitophagy to reduce the number of mitochondria and subsequently inhibit both mitochondrial and glycolytic bioenergetics, which eventually leads to ATP starvation death. Moreover, Ir‐Rhein can overcome cisplatin resistance. Co‐incubation experiment, 3D tumor spheroids experiment and transcriptome analysis reveal that Ir‐Rhein shows promising antiproliferation performance for cisplatin‐resistant cancer cells with the regulation of platinum resistance‐related transporters. To our knowledge, this is a new strategy to overcome metallodrug resistance with a mitochondria‐relevant treatment.

Half-sandwich Os-arene complexes exhibit promising anticancer activity, but their photochemistry has hardly been explored. To exploit the photocytotoxicity and photochemistry of Os-arenes, O,O-chelated complexes [Os(η 6 -p-cymene)(Curc)Cl] (OsCUR-1, Curc = curcumin) and [Os(η 6 -biphenyl)(Curc)Cl] (OsCUR-2), and N,N-chelated complexes [Os(η 6 -biphenyl)(dpq)-I]PF 6 (OsDPQ-2, dpq = pyrazino[2,3-f ][1,10]phenanthroline) and [Os(η 6 -biphenyl)(bpy)I]PF 6 (OsBPY-2, bpy = 2,2′-bipyridine), have been investigated. The Os-arene curcumin complexes showed remarkable photocytotoxicity toward a range of cancer cell lines (blue light IC 50 : 2.6−5.8 μM, photocytotoxicity index PI = 23−34), especially toward cisplatin-resistant cancer cells, but were nontoxic to normal cells. They localized mainly in mitochondria in the dark but translocated to the nucleus upon photoirradiation, generating DNA and mitochondrial damage, which might contribute toward overcoming cisplatin resistance. Mitochondrial damage, apoptosis, ROS generation, DNA damage, angiogenesis inhibition, and colony formation were observed when A549 lung cancer cells were treated with OsCUR-2. The photochemistry of these Osarene complexes was investigated by a combination of NMR, HPLC-MS, high energy resolution fluorescence detected (HERFD), Xray adsorption near edge structure (XANES) spectroscopy, total fluorescence yield (TFY) XANES spectra, and theoretical computation. Selective photodissociation of the arene ligand and oxidation of Os(II) to Os(III) occurred under blue light or UVA excitation. This new approach to the design of novel Os-arene complexes as phototherapeutic agents suggests that the novel curcumin complex OsCUR-2, in particular, is a potential candidate for further development as a photosensitizer for anticancer photoactivated chemotherapy (PACT).