The Membrane-camouflaged Nanosystem Based On Carbon Quantum Dots Treated Alzheimer’s Disease By Inhibiting And Eliminating Aβ1-42

Alzheimer’s disease（AD）is a neurodegenerative disease with complex pathological mechanisms.The main pathological manifestations are abnormal deposition ofβ-amyloid plaques and neurofibrillary tangles in the brain,accompanied by a series of related reactions such as neuronal loss,mitochondrial dysfunction,and neuroinflammation.Most AD patients may have symptoms such as memory loss in the early stage of the disease.As the disease progresses,patients will also have symptoms such as cognitive impairment.At present,the treatment of AD is still a challenge.Commonly used drug treatments include acetylcholinesterase inhibitors and NMDA receptor antagonists.These drugs can improve symptoms and delay disease progression,but cannot cure the disease.In addition,some drugs targetingβ-amyloid are undergoing clinical trials,which may become a new direction for the treatment of Alzheimer’s disease in the future.In this paper,a nitrogen-doped carbon quantum dot（CQD）was synthesized.It has a small size（less than 10 nm）and can efficiently penetrate the blood-brain barrier（BBB）.Its surface has rich nitrogen-containing functional groups,which can chelate with metal copper ions,delay and reduce Cu²⁺-induced Aβaggregation and neuronal cell oxidative damage.At the same time,CQD has excellent photothermal heating performance in the near-infrared region（700-900 nm）,which can be applied to the treatment of photothermal depolymerization of mature Aβfibrils.However,due to the immune response caused by nanoparticles entering the human body,nanoparticles will be quickly excreted,reducing their efficacy.There have been many reports that the modification of cell membrane-like liposomes and cell membranes has enabled nanoparticles to have immune escape and long circulation functions,thereby enhancing the effectiveness of nano-therapeutic systems.Liposome is a kind of cell membrane material with high biocompatibility and good affinity,which can improve the transport efficiency of drugs in vivo and reduce the toxic and side effects of drugs.Red blood cell membrane（RBC-M）and macrophage membrane（RAW-M）have the advantages of liposomes.At the same time,because they are both endogenous substances,they can more effectively avoid immune rejection.A variety of receptor molecules on the surface of the cell membrane can be recognized and taken up by recipient cells to enhance the targeting of nano-therapy systems.Liposome and cell membrane modified carbon quantum dots can achieve multi-target synergistic treatment of AD,delay and reduce the incidence rate and level of AD model mice,and improve the learning and memory ability of AD model mice to a certain extent.In this study,CQD was used as the substrate material,and liposome,erythrocyte membrane and macrophage membrane were selected for outer modification to construct a stable multi-functional nanoplatform of carbon quantum dot bionic system,and a series of characterization and in vitro and in vivo evaluation were carried out.The specific research results are as follows:（1）A lipid-modified CQD composite nanomaterial system was constructed and successfully applied to the combination of phototherapy and chemotherapy for Alzheimer’s disease for the first time.Firstly,N-doped carbon quantum dots（CQD）were successfully synthesized using citric acid and urea as raw materials.After liposome and cell membrane modification on the surface of CQD,the structure was characterized by TEM,TEM-mapping particle size potential and FTIR.The results showed that CQD-lipid,CQD-RBC and CQD-RAW were successfully prepared,and CQD was successfully encapsulated in lipid and cell membrane.The in vitro stability experiment proved that the modified composite material showed good stability.The liposome system showed good dispersion and stability in the physiological environment before and after drug loading.In addition,the excellent photothermal performance of the material can rise the temperature to the ideal photothermal temperature in a relatively short time with a small power to achieve the purpose of digesting mature Aβfibers.In vitro drug loading and release experiments showed that the liposome system had a high drug loading rate,and the release rate of Cur was accelerated after near-infrared light irradiation.Cell uptake and toxicity experiments showed that the composite material could be successfully taken up by cells without obvious cytotoxicity.The inhibition level of the material on the cytotoxicity of Aβaggregates showed a certain concentration dependence.At the same time,the photothermal depolymerization ability of mature Aβfibers also had a concentration-dependent characteristic.In addition,the investigation of in vivo brain thermal imaging further proved that the composite material can cross the BBB more efficiently with the help of near-infrared irradiation and enter the brain to improve the therapeutic effect.（2）Since the blood-brain barrier prevents most macromolecular drugs from entering the brain,safe and effective penetration through the BBB is the key to the treatment of AD.In the third and fourth chapters,we evaluated the in vivo animal experiments of CQD-RBC and CQD-RAW nano-drug systems.Animal behavioral experiments and immunohistochemical experiments confirmed that the nano-drug system can act on the lesion site of AD through BBB,and improve the cognitive function and learning and memory impairment of AD mice by inhibiting Cu²⁺-induced Aβmonomer aggregation,photothermal decomposition to remove Aβfibers,alleviating peripheral nerve inflammation and improving neuronal damage.