Construction And Biological Applications Of Controlled Stimulus-Responsive ROS-Generating Nanomaterials

Reactive oxygen species（ROS）was a class of highly reactive substances,including superoxide anion radicals(O₂^·-),singlet oxygen（¹O₂）,and hydroxyl radicals（·OH）,and hydrogen peroxide（H₂O₂）.ROS was of great significance for the physiological activities of organisms and the treatment of diseases,on the one hand,ROS with high oxidative activity such as O₂^·-,·OH could oxidize biological macromolecules,so it plays an active role in the diagnosis and treatment of cancer,neurodegenerative diseases,bacterial infections and other diseases;ROS was also a kind of intracellular second messenger,based on its oxidation,could oxidize and activate cysteine-containing proteins in the metabolic activities of organisms,such as cell division,immune system activation,muscle cell contraction,nerve cell electrical signal transmission,endocrine hormone secretion,stem cell directed differentiation,etc.However,the reactive activity of ROS was a double-edged sword.Although it could play a role in disease treatment and signal transduction,uncontrolled excessive ROS would lead to serious consequences,such as inflammation in normal tissues,cell apoptosis,senescence,and even cancer.How to control the biological application of ROS reasonably and effectively is always an important research direction.Thanks to the rapid development of nanotechnology in recent decades,a variety of nanomaterials have emerged,such as supramolecular self-assembling materials and metal-organic framework materials（MOFs）.Supramolecular self-assembled nanomaterials have many advantages,such as convenient synthesis,strong modifiability,good compatibility,and adjustable morphology.More and more supramolecular self-assembly nanomaterials were widely functionalized and used in various fields.In addition,MOFs-based materials have also achieved a lot of results,thanks to the unique porous structure of MOFs,MOFs have amazing specific surface area,and the modifiability of organic ligands brings a variety of functional derivatives to MOFs,so it has become a star material in the field of catalysis,such as photocatalytic production of H₂,electrocatalytic carbon sequestration and redox catalytic treatment of pollutants and other function-derived MOFs materials.To effectively control the generation of ROS,ROS producing supramolecular nanomaterials and ROS-generating MOFs have been developed.At present,the control methods of ROS producing supramolecular nanomaterials can be divided into chemical regulation,optical regulation,thermal regulation,magnetic regulation,etc.These regulatory methods effectively solve the adverse reactions caused by uncontrollable ROS,but there are still some obstacles to be overcome.For example,nanomaterials using ROS to treat cancer often have limited therapeutic effect due to the antioxidant mechanism of cancer cells;Materials used to generate ROS to activate intracellular physiological signals suffer from insufficient efficiency.Based on the above thinking,we combined nanotechnology with ROS,explored and developed two controllable stimulus-responsive ROS-generating nanomaterials,and explored two different directions of in vivo applications according to the function of ROS,as follows:1.Construction and anti-cancer application of chemical stimulation response ROS-generating nanocapsules.In this part of the work,we synthesized nanocapsule IM-Se-Ph NPs by supramolecular self-assembly method with selenoenzyme mimic and Zn²⁺self-assembly,and the coordination bonds of this nanocapsule have ATP responsiveness and will dissolve under the action of ATP.Based on the above characteristics,we further functionalized this nanocapsule,loaded with natural glucose oxidase（GOx）inside,and attached tannin-Fe³⁺（TA-Fe）nanocoated material to its outer surface to obtain composite nanomaterials GOx@IM-Se-Ph@TA-Fe NPs.We used GOx@IM-Se-Ph@TA-Fe NPs for anti-tumor therapy,when GOx@IM-Se-Ph@TA-Fe NPs entered the cell,they were dissolved under the action of ATP to release GOx,the selenomic IM-Se-Ph,and TA and Fe³⁺.Among them,GOx consumes glucose to produce a large amount of H₂O₂,and IM-Se-Ph catalyzes the degradation reaction of GSH in a large amount of H₂O₂.TA reduced Fe³⁺to Fe²⁺,then,Fe²⁺-mediated CDT generated·OH.Ultimately,due to the low level of GSH in the tumor,the excess production of·OH avoid depletion and promoted apoptosis of tumor cells.2.Construction of intelligent light control H₂O₂-generating MOFs materials.In this chapter,we were inspired by the molecular function of the ROS messenger to develop novel photocatalytic H₂O₂-generating nanomaterials for subsequent work on cell signaling.It was found that the main means of catalytic production of H₂O₂ in industry is redox catalysis of anthracene structural derivatives,and many literatures reported that anthracene structure has high catalytic efficiency in photocatalytic production of H₂O₂.Based on the above thinking,we have modified anthracene small molecules that are not suitable for biological applications through nanotechnology,and finally obtained intelligent light controlled H₂O₂-generating MOFs materials.At the beginning of the transformation process,we constructed a molecular library containing 13 benzene ring molecules,photocatalyzed the production of H₂O₂.Based on the anthene molecular structure,we modified the anthrene molecular structure into organic ligands of MOFs through nanotechnology modification,and finally obtained anthrene MOFs nanomaterials.Compared with small molecules,the photocatalytic production capacity of anthracene MOFs is improved by more than 100%,and the catalyst inactivation defect is overcome.We illustrate the principle of anthene photocatalytic production of H₂O₂ by cyclic voltammetry and band diagrams.The intelligent light controlled H₂O₂-generating MOFs material developed by us can quickly and efficiently produce H₂O₂,which can become a powerful research tool in the field of cell signaling.3.Intelligent light control H₂O₂-generating MOFs on cell and biological behavior regulation research.As the second signal in the body,ROS can activate and transmit biological signals,especially the relatively mild oxidation ability of H₂O₂,and has become an important molecule for intracellular signal transmission.This chapter of work is inspired by the messenger molecule H₂O₂ and based on the previous chapter intelligent light control H₂O₂-generating MOFs materials,we have studied the regulation of cell and biological behavior.At the single-cell level,we have confirmed light control H₂O₂-generating MOFs can effectively control the excitation and transmission of Ca²⁺signals in single cells and have universal applicability to a variety of cells.At the multicellular level,we successfully triggered the excitation and transmission of Ca²⁺signals in the"point stimulation group response"of HL-1 cells,that is,by stimulating a single cell,the excitation and transmission of Ca²⁺signals in a certain range of surrounding cells.At the same time,we further applied the light control H₂O₂-generating MOFs material to ex vivo tissues,and found that the Ca²⁺signal in the tissue was transmitted farther.Our study of the transport mechanism may be that H₂O₂activates Ca²⁺channels in the endoplasmic reticulum,resulting in Ca²⁺signal activation,and diffusion to surrounding cells through ATP to trigger population responses.In animal behavior studies,we applied light control H₂O₂-generating MOFs to visually deficient tadpoles,which can regain photosensitivity in visually deficient tadpoles,and at the same time trigger non-conditioned spinal nerve excitability in Xenopus frogs.Our intelligent and at the same time trigger non-conditioned spinal nerve excitability in Xenopus frogs’light control H₂O₂-generating MOFs have the advantages of high efficiency,reproducibility and low toxicity,and the use of light stimulation to produce H₂O₂ can regulate the microscopic and macroscopic behavior of organisms.This material provides new ideas for the study of biological signals,and at the same time gives our understanding in chemistry,materials science,biomolecular and other multidisciplinary research.