Study On Reactive Oxygen Species Regulating Strategies-Based Multifunctional Delivery Systems For Tumor And Cardiovascular Diseases Treatment

Reactive oxygen species（ROS）is a collective term that describes the chemical species formed upon incomplete reduction of oxygen,which plays an essential role in mediating various physiological and pathological functions.The balance of ROS generation and elimination is necessary for metabolism.In some exogenous certain stimuli,disruption of ROS homeostasis leads to oxidative stress that may disrupt in a number of downstream pathological dysfunctions,such as tumor and cardiovascular diseases.Recently,various types of ROS-regulating drugs have been investigated.Although these agents exhibit substantiated therapeutic effects on ROS related diseases,limited success has been achieved because of their poor solubility,low delivery efficiency and adverse effects.Thanks to the remarkable advances of nanotechnology,great varieties of nanomaterials with ROS-regulating capabilities have been explored for new and effective ROS-related nanotherapeutic modalities or nanomedicines.On this basis,we have designed four ROS-modulating nano-delivery systems and explored their therapeutic effects on diseases in both ROS generation/scavenging by using tumor and atherosclerosis as models,respectively.We analyzed their structural and functional properties,verified their therapeutic mechanisms and carried out a comprehensive study on ROS upregulating/downregulating strategies for precise disease treatment.In terms of regulating ROS generation,tumor cells are more sensitive to ROS than normal tissues due to their inefficient clearance of ROS,that is,ROS has selective killing effect on tumor cells.By increasing the ROS content,tumor cells can be damaged and inhibited.Herein,we designed glucose-oxidase（GOx）-loaded Au-Ag bio-breakable nanozymes,which could trigger a near-infrared（NIR）-II-driven plasmon-enhanced cascade catalytic reaction through regulating tumor microenvironment（TME）for ROS mediated tumor catalytic therapy.Firstly,GOx can effectively trigger the generation of gluconic acid and hydrogen peroxide,thus depleting nutrients in the tumor cells as well as modifying TME to provide conditions for subsequent peroxidase-like activity.Then,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.Due to the heterogeneity of the tumor,the limited penetration ability of nanomedicine in deep tumor affects their therapeutic efficacy.To overcome this limitation,we developed sulfur dioxide（SO₂）prodrug loaded Au-Ag hollow nanotriangles for deep tumor therapy.Upon NIR laser irradiation,this nanotriangles produced plenty of heat for photothermal therapy,while the acidic condition in tumor cells induced on-demand SO₂ release for deep tumor therapy.More importantly,the combined therapy could simultaneously upregulate the expression of apoptosis factor Bax as well as downregulate Bcl-2 in mitochondria,which would induce an increase of Caspase-3 expression to accelerate the apoptosis of tumor cells,thereby achieving a win-win cooperation.In terms of regulating ROS scavenging,oxidative stress has become an important part of the atherosclerotic plaque formation.The strong oxidation of ROS can directly or indirectly damage nucleic acids and proteins,leading to disturbance of lipid metabolism and promoting atherosclerotic lesions.Herein,we designed aloperine（ALO）-loaded and hyaluronic acid（HA）-modified palladium（Pd）octahedral nanozymes（Pd@HA/ALO）that could synergistically scavenge 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,Pd@HA/ALO could actively accumulate in atherosclerotic plaques.The antioxidative effects were mediated by their intrinsic enzyme-like activities capable of effective scavenging of ROS.The anti-inflammatory effects were mediated by NIR-triggered ALO release leading to inhibition of COX-2 expression.Importantly,the combined therapy could 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 realizing atherosclerosis treatment.Moreover,the imbalance between lipid uptake and efflux induced by oxidative stress plays a dominant role at all stages of atherosclerotic development.However,only limited therapeutic efficacy of lipid-regulating agents has been achieved because of their poor solubility,single lipid downregulating mechanism and low delivery efficiency.Herein,we propose a“coupling hardness with softness”strategy by using palladium hydride nanopocket cubes to regulate lipid uptake and efflux for atherosclerosis treatment.The palladium nanopocket cubes played the hardness role in efficiently scavenging ROS via their innate antioxidant enzyme activities.The NIR-II controlled the release of hydrogen upregulated PPAR-γ-mediated cholesterol transport pathway,which played the softness role.Consequently,ROS scavenging reduced lipid uptake and promoted cholesterol transport increased lipid efflux,resulting in the amplified-inhibition of foam cells.In summary,this study has confirmed the ROS-regulating activities of four nanoplatforms and elucidated their therapeutic mechanisms for tumors and atherosclerosis,hoping to provide evidence and theoretical frames for subsequent development of ROS-associated nano-delivery systems.