The Research And Application Of Extracellular Vesicles As Nano-Carrier For Targeted Drug Delivery

Extracellular vesicles(EVs)are a heterogeneous collection of membrane-bound carries released by almost all types of cells.EVs includs apoptotic bodies,microvesicles and exosomes.Under normal physiological conditions,the release of EVs plays a role in information exchange and cargoes transmission between cell to cell communication,such as proteins and nucleic acids.Under pathological conditions,they appear to participate in a variety of diseases,most notably cancer and cardiovascular disease,and plays an important role in promoting disease progression.Besides,EVs could cross multiple physiological barriers of the body(such as blood-brain barrier,BBB),and get into the blood circulation system and spread to distance tissue.Due to the good biocompatibility,low immunogenicity in blood circulation,as well as the intrinsic targeting ability,EVs has become an ideal nano-drug delivery vector which has also gained considerable scientific interest.Given the facts that,EVs has significant advantages as a nano-drug carrier,the mechanism by which EVs can be nearly non-immunogenic and have such a long circulation time remains elusive.Meanwhile,It is important to make EVs to be with targeted ability,as well as to expand the application of EVs in drug delivery to promot the clinical transformation.In this study,the mechanism that the advantages of EVs as a drug carrier were clarified by using proteomic profiling technology from the point of view of the protein corona,making the EVs be with targeted ability by using genetic engineering technology,and load biomacromolecules(e.g.oncolytic adenovirus)in the engineered EVs for targeted delivery,which expand the application of EVs in drug delivery and cancer treatment as well as promoting the clinical transformation of EVs.The main research of this paper are summarized as follows:(1)In Chapter 1,We summarized the research status of extracellular vesicles(EVs)as drug carriers,introduced the purification methods of extracellular vesicles in detail and investigated the preparation methods of extracellular vesicles loaded with nano-drugs,and summarized the research status of clinical diagnosis and treatment of diseases with drug-loaded EVs.According to the above content,we determined the research direction of this study.(2)In Chapter 2,we summarized the commonly used experimental methods and techniques which were used throughout the following research.(3)In Chapter 3,we evaluated the protein coronal(PC)formed by EVs interacts with blood proteins in blood circulation system by using proteomic profiling technology.Then,bioinformatics analysis was performed to investigate thoroughly about the mechanism by which EVs can be nearly non-immunogenic and have such a long circulation time as a drug carrier.Furthermore,we had found out the key protein in the protein-protein network that forms the protein corona.(4)In Chapter 4,we successfully synthesized an agile and versatile oncolytic adenovirus(OA)delivery platform--bioengineered cell membrane nanovesicles(BCMNs)that harbor targeting ligands on the EVs surface to achieve robust anti-viral immune shielding and targeting capabilities for oncolytic virotherapy.The platform is applicable for the selective targeting of specific cancer cells and minimal antiviral immune response,which limit current clinical virotherapies for cancer.This novel BCMNs nanoplatform could potentially provide a valuable tool for future clinical translation to fabricate smart OA delivery systems.