Ambient Synthesis Of Nanoscale Covalent Organic Frameworks For Redox Biomedical Applications

Cancer nanomedicine is one of the most promising domains that has emerged in the continuing search for cancer diagnosis and treatment.The rapid development of nanomaterials and nanotechnology provide a vast array of materials for use in cancer nanomedicine.Among the various nanomaterials,covalent organic frameworks（COFs）,which are porous crystalline networks constructed through the covalent bonding of organic monomers containing light elements（e.g.,C,N,O,H,and B）,are becoming an attractive class of upstarts owing to their structural regularity,high crystallinity,inherent porosity,extensive functionality,design flexibility,and good biocompatibility.The frameworks,linkages,pore structures,and even defects of COFs can be modified with one or more functional components,thus enabling their rational and function-oriented design for antitumor nanotherapy.Research on COF-based nanosystems covers a rapidly growing range of topics,including chemotherapy,radiotherapy,immunotherapy,phototherapy,chemodynamic therapy（CDT）,etc.In Chapter 1,a variety of COF functionalization approaches for oncotherapy,including covalent functionalization,host-guest chemistry,and metalation,are delineated.The potential of COF-based nanoplatforms as multifunctional nanomedicines is emphasized.In Chapter 2,a COF-based therapeutic system was developed for enhancing CDT via a redox dyshomeostasis therapeutic strategy.This system was termed RSL3@COF-Fc,where ferrocenecarboxaldehyde as a Fenton-like reaction catalyst and RSL3 as a small-molecule covalent inhibitor of GPX4 were integrated into COF nanoparticles.Once RSL3@COF-Fc was endocytosed by tumor cells,the gradually released RSL3 inhibited GPX4—which is the core checkpoint of the tumor cell antioxidant system—to disturb redox homeostasis,while Fc induced·OH production via Fenton-like reactions,resulting in lipid peroxidation.Based on the premise of cell redox dyshomeostasis,effective repair of oxidative damage cannot be achieved even if there is a high content of GSH in the cells,thus allowing toxic ROS accumulation.Ultimately,RSL3@COF-Fc led to plasma membrane,lysosomal,and mitochondrial damage and subsequent ferroptosis of tumor cells,and was less toxic to normal cells.These results were confirmed in experiments at the molecular and cellular levels and in an animal model.In Chapter 3,the ambient synthesis of the iminium-linked cationic ABMI-COF via a three-component reaction is reported.Through ion exchange of the iodide counterion with 3-bromopyruvate,a hexokinase 2（HK2）inhibitor,multifunctional ABMBP-COF was generated.Both ABMI-COF and ABMBP-COF possessed high si RNA adsorption capacity(greater than 1nmol mg^-1)and could escape from lysosomes.More importantly,after being loaded with solute carrier family 7 member 11（SLC7A11）si RNA,si RNA@ABMBP-COF could silence SLC7A11and inhibit HK2,consequently achieving antitumor effects via ferroptosis and apoptosis.In Chapter 4,a cationic COF with iodide counterions prepared by a three-component reaction is reported.The generated TDI-COF could be a tumor radiosensitizer to enhance colorectal cancer radiotherapy.The good X-ray absorption capacity of TDI-COF allowed it to promote radiation-induced DNA damage and lipid peroxidation,and induce ferroptosis that inhibits cell proliferation and tumor growth.This study is not only the first example of metal-free COFs for radiotherapy,but also highlights their great potential as radiotherapy radiosensitizers.In Chapter 5,the room-temperature synthesis of an iodine-and ferrocene-loaded COF nanozyme,termed TADI-COF-Fc,for the enhancement of radiotherapeutic efficacy in the treatment of radioresistant esophageal cancer,is reported.The iodine atoms on the COF-framework not only exerted a direct effect on radiotherapy,increasing its efficacy by increasing X-ray absorption,but also promoted the radiolysis of water,which increased the production of reactive oxygen species.In addition,the ferrocene surface decoration disrupted redox homeostasis by increasing the levels of hydroxyl and lipid peroxide radicals and depleting intracellular antioxidants.Both in vitro and in vivo experiments substantiated the excellent radiotherapeutic response of TADI-COF-Fc.This study demonstrates the potential of COF-based multinanozymes as radiosensitizers and suggests a possible integration strategy for oncotherapy.