Enhanced macrophage polarization induced by COX-2 inhibitor-loaded Pd octahedral nanozymes for treatment of atherosclerosis

Inhibition of foam cell formation is considered a promising treatment method for atherosclerosis,the leading cause of cardiovascular diseases worldwide.However,currently available therapeutic strategies have shown unsatisfactory clinical outcomes.Thus,herein,we design aloperine(ALO)-loaded and hyaluronic acid(HA)-modified palladium(Pd)octahedral nanozymes(Pd@HA/ALO)that can synergistically scavenge reactive oxygen species(ROS)and downregulate cyclooxygenase-2(COX-2)expression to induce macrophage polarization,thus inhibiting foam cell formation to attenuate atherosclerosis.Due to the targeted effect of HA on stabilin-2 and CD44,which are overexpressed in atherosclerotic plaques,Pd@HA/ALO can actively accumulate in atherosclerotic plaques.Subsequently,the antioxidative effects of Pd octahedral nanozymes are mediated by their intrinsic superoxide dismutase-and catalase-like activities capable of effective scavenging of ROS.In addition,anti-inflammatory effects are mediated by controlled,on-demand near-infrared-triggered ALO release leading to inhibition of COX-2 expression.Importantly,the combined therapy can promote the polarization of macrophages to the M2 subtype by upregulating Arg-1 and CD206 expression and downregulating expression of TNF-α,IL-1βand IL-6,thereby inhibiting atherosclerosis-related foam cell formation.In conclusion,the presented in vitro and in vivo data demonstrate that Pd@HA/ALO enhanced macrophage polarization to reduce plaque formation,identifying an attractive treatment strategy for cardiovascular disease.

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.

Rod-shape inorganic biomimetic mutual-reinforcing MnO2-Au nanozymes for catalysis-enhanced hypoxic tumor therapy

Biomimetic nanozymes possessing natural enzyme-mimetic activities have been extensively applied in nanocatalytic tumor therapy.However,engineering hybrid biomimetic nanozymes to achieve superior nanozyme activity remained to be an intractable challenge in hypoxic tumors.Herein,a rod-like biomimetic hybrid inorganic MnO2-Au nanozymes are developed,where MnO2 and ultrasmall Au nanoparticles(NPs)are successively deposited on the mesoporous silica nanorod to cooperatively improve the O2 content and thermal sensitivity of hypoxic solid tumors guided by multi-modal imaging.Under the catalyzing of MnO2,the intratumoral H2O2 is decomposed to greatly accelerate O2 generation,which could boost the curative effect of radiation therapy(RT)and further enhance the Au-catalyzed glucose oxidation.Mutually,the Au NPs can steadily and efficiently catalyze the oxidation of glucose in harsh tumor microenvironment,thus sensitizing tumor cells to thermal ablation for mild photothermal therapy and further promoting the catalytic efficiency of MnO2 with the self-supplied H2O2/H+.As a result,this mutual-reinforcing cycle can endow the nanoplatform with accelerated O2 generation,thus alleviating hypoxic environment and further boosting RT effect.Furthermore,acute glucose consuming can induce downregulation expression of heat shock protein(HSP),achieving starvation-promoted mild photothermal therapy.This synthesized hybrid nanozymes proves to be a versatile theranostic agent for nanocatalytic cancer therapy.

NIR-II driven plasmon-enhanced cascade reaction for tumor microenvironment-regulated catalytic therapy based on bio-breakable Au-Ag nanozyme

Emerging nanozymes with natural enzyme-mimicking catalytic activities have inspired extensive research interests due to their high stability,low cost,and simple preparation,especially in the field of catalytic tumor therapy.Here,bio-breakable nanozymes based on glucose-oxidase(GOx)-loaded biomimetic Au–Ag hollow nanotriangles(Au–Ag–GOx HTNs)are designed,and they trigger an near-infrared(NIR)-II-driven plasmon-enhanced cascade catalytic reaction through regulating tumor microenvironment(TME)for highly efficient tumor therapy.Firstly,GOx can effectively trigger the generation of gluconic acid(H+)and hydrogen peroxide(H2O2),thus depleting nutrients in the tumor cells as well as modifying TME to provide conditions for subsequent peroxidase(POD)-like activity.Secondly,NIR-II induced surface plasmon resonance can induce hot electrons to enhance the catalytic activity of Au–Ag–GOx HTNs,eventually boosting the generation of hydroxyl radicals(•OH).Interestingly,the generated H2O2 and H+can simultaneously induce the degradation of Ag nanoprisms to break the intact triangle nanostructure,thus promoting the excretion of Au–Ag–GOx HTNs to avoid the potential risks of drug metabolism.Overall,the NIR-II driven plasmon-enhanced catalytic mechanism of this bio-breakable nanozyme provides a promising approach for the development of nanozymes in tumor therapy.