The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) can kill cancer cells more efficiently as compared with PTT or PDT treatment alone. In this work, we use nanohybrid rGO-Ru-PEG composed of reduced nanographene oxide (rGO) sheet and a phosphorescent polyethylene glycol modified Ru(II) complex (Ru-PEG) for combined PTT and PDT of cancer. Photosensitizer and imaging agent Ru-PEG is decorated onto delivery and PTT agent rGO via π-π stacking and hydrophobic interactions. The chemical structure and morphology have been characterized by various methods. The release of Ru-PEG from rGO surface is pH-dependent, and irradiation can increase the release rate considerably. The combined effects of PDT and PTT have been evaluated by cytotoxicity assay under serial irradiation at 808 nm (PTT) and 450 nm (PDT). Mechanism investigation shows that the nanohybrid can induce apoptosis through generation of reactive oxygen species (ROS) and cathepsin-initiated apoptotic signaling pathways under light excitation. rGO-Ru-PEG can be applied to in vivo photothermal imaging, and high treatment efficacy was achieved for in vivo antitumor experiments when irradiated with an 808 nm laser and a 450 nm laser. Our work provides an effective strategy for the construction of multifunctional imaging and phototherapeutic nanohybrids for the treatment of cancer.

Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir­(III) complexes Ir1–Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1–Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido­[3,2-a:2′,3′-c]­phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance.

Background & Aims Obesity promotes the development of nonalcoholic fatty liver diseases (NAFLDs), yet not all obese patients develop NAFLD. The underlying causes for this discrepancy remain elusive. LPGAT1 is an acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG), a mitochondrial phospholipid implicated in various metabolic diseases. Here, we investigated the role of LPGAT1 in regulating the onset of diet-induced obesity and its related hepatosteatosis because polymorphisms of the LPGAT1 gene promoter were strongly associated with susceptibility to obesity in Pima Indians. Methods Mice with whole-body knockout of LPGAT1 were generated to investigate the role of PG remodeling in NAFLD. Results LPGAT1 deficiency protected mice from diet-induced obesity, but led to hepatopathy, insulin resistance, and NAFLD as a consequence of oxidative stress, mitochondrial DNA depletion, and mitochondrial dysfunction. Conclusions This study identified an unexpected role of PG remodeling in obesity, linking mitochondrial dysfunction to NAFLD.

Recently, phosphorescent iridium complexes have demonstrated great potential as anticancer and imaging agents. Dopamine is a melanin‐like mimic of mussel adhesive protein that can self‐polymerize to form polydopamine (PDA) nanoparticles that demonstrate favorable biocompatibility, near‐infrared absorption, and photothermal effects. Herein, PDA nanoparticles are functionalized with β‐cyclodextrin (CD) substitutions, which are further assembled with adamantane‐modified arginine‐glycine‐aspartic acid (Ad‐RGD) tripeptides to target integrin‐rich tumor cells. The thus formed PDA‐CD‐RGD nanoparticles can deliver a phosphorescent iridium(III) complexes LysoIr ([Ir(ppy)2(l)]PF6, ppy = 2‐phenylpyridine, L = (1‐(2‐quinolinyl)‐β‐carboline) to form a theranostic platform LysoIr@PDA‐CD‐RGD. It is demonstrated that LysoIr@PDA‐CD‐RGD can be applied for targeted combined cancer photothermal‐chemotherapy and thermal/photoacoustic/two‐photon phosphorescence lifetime imaging under both in vitro and in vivo conditions. This work provides a useful strategy to construct multifunctional nanocomposites for the optimization of metal‐based anticancer agents for further biomedical applications.

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Ruthenium complexes are promising photosensitizers (PSs), but their clinical applications have many limitations. Here, a multifunctional nano‐platform PDA‐Pt‐CD@RuFc formed by platinum‐decorated and cyclodextrin (CD)‐modified polydopamine (PDA) nanoparticles (NPs) loaded with a ferrocene‐appended ruthenium complex (RuFc) is reported. The NPs can successfully deliver RuFc to the tumor sites. The release of RuFc from the NPs can be triggered by low pH, photothermal heating, and H2O2. The combined photodynamic and photothermal therapy (PDT‐PTT) mediated by PDA‐Pt‐CD@RuFc NPs can overcome the hypoxic environment of tumors from several aspects. First, the platinum NPs can catalyze H2O2 to produce O2. Second, vasodilation caused by photothermal heating can sustain the oxygen supplement. Third, PDT exerted by RuFc can also occur through the non‐oxygen‐dependent Fenton reaction. Due to the presence of PDA, platinum NPs, and RuFc, the nanosystem can be used in multimodal imaging including photothermal, photoacoustic, and computed tomography imaging. The NPs can be excited by the near‐infrared two‐photon light source. Moreover, the combined treatment can improve the tumor microenvironments to obtain an optimized combined therapeutic effect. In summary, this study presents a tumor‐microenvironment‐adaptive strategy to optimize the potential of ruthenium complexes as PSs from multiple aspects.

Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for membrane structure, respiration, dynamics, and mitophagy. Oxidative damage of CL by reactive oxygen species is implicated in the pathogenesis of Parkinson's disease (PD), but the underlying cause remains elusive. This work investigated the role of ALCAT1, an acyltransferase that catalyzes pathological remodeling of CL in various aging‐related diseases, in a mouse model of PD induced by 1‐methyl‐4‐phenyl‐1,2,4,6‐tetrahydropyridine (MPTP). We show that MPTP treatment caused oxidative stress, mtDNA mutations, and mitochondrial dysfunction in the midbrain. In contrast, ablation of the ALCAT1 gene or pharmacological inhibition of ALCAT1 prevented MPTP‐induced neurotoxicity, apoptosis, and motor deficits. ALCAT1 deficiency also mitigated mitochondrial dysfunction by modulating DRP1 translocation to the mitochondria. Moreover, pharmacological inhibition of ALCAT1 significantly improved mitophagy by promoting the recruitment of Parkin to dysfunctional mitochondria. Finally, ALCAT1 expression was upregulated by MPTP and by α‐synucleinopathy, a key hallmark of PD, whereas ALCAT1 deficiency prevented α‐synuclein oligomerization and S‐129 phosphorylation, implicating a key role of ALCAT1 in the etiology of mouse models of PD. Together, these findings identify ALCAT1 as a novel drug target for the treatment of PD.

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