Iron-based and BRD_(4)-downregulated strategy for amplified ferroptosis based on pH-sensitive/NIR-Ⅱ-boosted nano-matchbox

Ferroptosis(FPT),a novel form of programmed cell death,is characterized by overwhelming iron/reactive oxygen species(ROS)-dependent accumulation of lipid peroxidation(LPO).However,the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent.To overcome this obstacle,the bromodomain-containing protein 4(BRD_(4))-inhibitor(+)-JQ1(JQ1)and iron-supplement ferric ammonium citrate(FAC)-loaded gold nanorods(GNRs)are encapsulated into the zeolitic imidazolate framework-8(ZIF-8)to form matchbox-like GNRs@JF/ZIF-8 for the amplified FPT therapy.The existence of matchbox(ZIF-8)is stable in physiologically neutral conditions but degradable in acidic environment,which could prevent the loaded agents from prematurely reacting.Moreover,GNRs as the drug-carriers induce the photothermal therapy(PTT)effect under the irradiation of near-infraredⅡ(NIR-Ⅱ)light owing to the absorption by localized surface plasmon resonance(LSPR),while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment(TME).On one hand,the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron(Fe^(3+)/Fe^(2+))and ROS to initiate the FPT treatment by LPO elevation.On the other hand,JQ1 as a small molecule inhibitor of BRD_(4)protein can amplify FPT through downregulating the expression of glutathione peroxidase 4(GPX4),thus inhibiting the ROS elimination and leading to the LPO accumulation.Both in vitro and in vivo studies reveal that this p H-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility.As a result,our study points out a PTT combined iron-based/BRD_(4)-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma(HCC).Hepatic stellate cell(HSC)activation is considered the main target for liver fibrosis therapy.However,the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis,including excessive extracellular matrix(ECM)deposition and hypoxia-induced imbalanced ECM metabolism.Herein,nilotinib(NIL)-loaded hyaluronic acid(HA)-coated Ag@Pt nanotriangular nanozymes(APNH NTs)were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis.APNH NTs efficiently eliminated intrahepatic reactive oxygen species(ROS)due to their inherent superoxide dismutase(SOD)and catalase(CAT)activities,thereby downregulating the expression of NADPH oxidase-4(NOX-4)and inhibiting HSCs activation.Simultaneously,the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment.Importantly,the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1(TIMP-1),thus synergistically remodeling the microenvironment of liver fibrosis.Notably,an in vivo study in CCl_(4)-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity.Taken together,the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

4T1 cell membrane-derived biodegradable nanosystem for comprehensive interruption of cancer cell metabolism

Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the replenishment pathway to maintain the tricarboxylic acid cycle ensuring energy supply,therefore inducing ineffective interruption of metabolic.Herein,we designed glutamine transporter antagonist L-γ-glutamyl-p-nitroanilide(GPNA)loaded and 4T1 cancer cell membrane coated iridium oxide nanoparticles(IrO_(2)-GPNA@CCM)to realize a comprehensive inhibition of tumor energy supply which synergistically mediated by glycolysis and glutamine cycle.IrO_(2)NPs were used to catalyze the O_(2)generation by facilitating the decomposition of endogenous H_(2)O_(2)in tumor cells,which further downregulated the expression of HIF-1αand PI3K/pAKT to interrupt the generation of lactate.Meanwhile,the loaded GPNA was released under NIR irradiation to bind to alanine-serine-cysteine transporter(ASCT2)for glutamine uptake suppression,therefore realizing the comprehensive dysfunction of cell metabolism.Moreover,both in vitro and in vivo results convinced the thorough energy inhibition effect based on Ir O_(2)-GPNA@CCM NPs,which provided an inspiring strategy for future construction of tumor therapeutic regimen.

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment response, and low toxicity, stimuli-responsive nano-based drug delivery systems(NDDSs) have been a promising approach in AS treatments. Herein, we will systematically summarize the recent advances in stimuli-responsive NDDSs for AS treatment, including internal stimuli(reactive oxygen species, enzyme, shear stress, and pH) and external stimuli(light, ultrasound, and magnetism) responsive NDDSs. Besides, we will also summarize in detail the classification of stimuli-responsive NDDSs for AS, such as organic NDDSs(e.g., lipid-based and polymer-based nanomaterials), inorganic NDDSs(e.g., metal-based nanoparticles and nonmetallic nanomaterials), and composite multifunctional NDDSs. Finally, the critical challenges and prospects of this field will also be proposed and discussed.