Construction Of New Nanozyme-Based Treatment Systems For Intensive Biomedical Applications

Nanozymes are nanomaterials with catalytic activities similar to natural enzymes.Thanks to their individual properties of both enzymology and nanomaterials,nanozymes have attracted massive attention in many fields,such as industrial catalysis and biomedicine.Though nanozymes have the advantages of facile preparation,high stability and high recycling efficiency when compared with natural enzymes,they also have some inherent defects,such as low catalytic activities,poor substrate selectivity,lack of targeting ability and unsatisfactory therapeutic effect when used in disease treatment.These shortcomings greatly limit their further biomedical applications.In this dissertation,a series of nanozyme-based composite systems were constructed from the design and biological applications of nanozymes to improve their catalytic activities and therapeutic effects in diseases such as cancer and bacterial infection.In addition,we also constructed a benign iron nanotrap to solve the biotoxicity problem caused by ferromagnetic nanoparticles,nanozymes and other metal-based nanomaterials in reprogramming tumor-associated macrophages.The main results are summarized as follows:1.Nanozymes have received considerable attention as alternatives of natural enzymes.However,the catalytic activity of nanozymes is often lower than that of natural enzymes,which largely limits their applications.Current methods utilized to improve the catalytic efficiency and substrate selectivity of nanozymes usually have some inherent drawbacks.Herein,a biomimetic strategy was developed to design Fe3+-doped mesoporous carbon nanospheres(Fe3+-MCNs)as a horseradish peroxidase(HRP)mimic to realize the structure and function mimicking of natural HRP.In this system,Fe3+ions could act as catalytic centers and carboxyl-modified mesoporous carbon nanospheres(MCNs-COOH)could be used to bind with substrates.As a result,Fe3+-MCNs showed higher enzymatic activity than that of Fe3O4 nanoparticles.Therefore,this strategy can contribute to the development of nanozymes and further understanding of the complicated enzymatic reactions in natural and biological systems.2.The insufficient intracellular H2O2 level in tumor cells is closely associated with the limited efficacy of chemodynamic therapy(CDT).Despite tremendous efforts,engineering CDT agents with a straightforward and secure H2O2 supplying ability remains a great challenge.Inspired by the balance of H2O2 generation and elimination in cancer cells,herein,a nanozyme-based H2O2 homeostasis disruptor is fabricated to elevate the intracellular H2O2 level through facilitating H2O2 production and restraining H2O2 elimination for enhanced CDT.In the formulation,the disruptor with superoxide dismutase-mimicking activity can convert O2·-to H2O2,promoting the production of H2O2.Simultaneously,the suppression of catalase activity and depletion of glutathione by the disruptor weaken the transformation of H2O2 to H2O.Thus,the well-defined system could perturb the H2O2 balance and give rise to the accumulation of H2O2 in cancer cells.The raised H2O2 level would ultimately amplify the Fenton-like reaction-based CDT efficiency.Our work not only paves a way to engineer alternative CDT agents with a H2O2 supplying ability for intensive CDT but also provides new insights into the construction of bioinspired materials.3.The widespread multidrug resistance resulting from the abuse of antibiotics motivates researchers to explore alternative methods to treat bacterial infections.Recently,the emergence of nanozymes has provided a potential approach to combat bacteria.Such nanozymes can mimic the functions of natural enzymes to produce highly toxic reactive oxygen species(ROS)as an antibacterial.However,the lack of effective interaction between nanozymes and bacteria,and the intrinsic short lifetime and diffusion distance of ROS greatly compromise their bactericidal activity.Furthermore,the dead bacteria left in the infected area can give rise to unexpected tissue inflammation.Herein,a nanozyme-hydrogel is constructed to realize reinforced antibacterials.The nanozyme-hydrogel with the traits of positive charge and macropore can capture and restrict bacteria in the range of ROS destruction.Significantly,by combining the near-infrared photothermal property of nanozymes,the nanozyme-hydrogel can achieve a synergistic bactericidal effect.More importantly,the nanozyme-hydrogel can eliminate bacteria and reduce the risk of inflammation.In consequence,the current work manifests an original strategy to improve the antibacterial performance of nanozymes,concurrently promote wound healing.4.Tumor-associated macrophages(TAMs)that infiltrate in most tumor tissues are closely correlated with proliferation and metastasis of tumor cells.Immunomodulation of TAMs from pro-tumorigenic M2 phenotype to anti-tumorigenic M1 phenotype is crucial for oncotherapy.Herein,an iron nanotrap was utilized to remodel TAMs for tumor growth inhibition.In the formulation,the ultrasmall nanotrap could capture and targetedly transport endogenous iron into TAMs even inside the tumor.Upon exposing to the lysosomal acidic conditions and intracellular H2O2,iron was released from the nanotrap and produced the generation of oxidative stress,which could reprogram TAMs.The activated M1 macrophages could induce immune responses and suppress tumor growth ultimately.Meanwhile,this metal-free nanotrap with degradability by H2O2 possessed favorable biocompatibility.Our work would promote the development of utilizing endogenous substances for secure treatment of various diseases.