An essential requirement here is to identify molecular scaffolds that present a tissue-targeting moiety while enabling loading with a therapeutic agent. These functions, however, can be introduced through the use of molecular and genetic engineering techniques. While EVs hold great promise in nanomedicine, endogenous EVs exhibit poor targeting to diseased cells and lack therapeutic cargo. Third, endogenously and/or exogenously produced EVs can be genetically engineered to facilitate drug loading and targeted delivery of biologics to diseased tissue. Second, EVs are capable of penetrating tissue to reach deep-seated cells, and there are known cases where they cross the blood-brain barrier (BBB). First, EVs are derived from human cells, so they are biocompatible and biodegradable and may evade rapid clearance by the immune system. As a new generation of nanomaterials, EVs may offer advantages over artificial nano-vehicles such as liposomes and polymers for targeted drug delivery and therapy. EVs are known to regulate tissue growth and organ development, modulate the immune response, mediate inflammation and viral infection, and promote cancer progression and metastasis. ![]() Consequently, they may be involved in shuttling specific signaling molecules, including proteins, nucleic acids, and lipids, to target cells in remote tissues. After being released from host cells, EVs may be found in significant numbers in blood plasma, lymph, ammonic fluid, saliva, urine, breast milk, and seminal fluid. EVs can also be divided into CD9 +, CD63 +, and CD81 + subtypes, each bearing specific surface markers. Mammalian EVs can be divided into two distinct types according to their membrane origin: for example, microvesicles have a diameter of 100–1000 nm and are formed by direct budding from the plasma membrane, while exosomes (50–150 nm) are released via exocytosis of multivesicular bodies (MVBs). In mammals, EVs are continuously synthesized and released to the extracellular environment in a constitutive and regulated manner. Scaffold-induced changes in the physical and functional properties of engineered EVs should therefore be considered in engineering EVs for the targeted delivery and uptake of therapeutics to diseased cells.Įxtracellular vesicles (EVs) are cell-derived nanocarriers that are thought to mediate cell-to-cell communication in prokaryotes and eukaryotes. Conclusion: We found that the incorporation of different molecular scaffolds in EVs altered their physicochemical properties, surface protein profiles, and cell-uptake functions. The results from cell uptake studies demonstrated that VSVG-engineered EVs were taken up by recipient cells to a greater degree than control EVs. Molecular profiling of surface markers in engineered EVs using on-chip assays showed the CD63-GFP scaffold decreased expression of CD81 on the membrane surface compared to control EVs, whereas its expression was mostly unchanged in EVs bearing CD9-, CD81-, or VSVG-GFP. Analysis of vesicle size revealed that the incorporation of each scaffold increased the average diameter of vesicles compared to unmodified EVs. Results: Fluorescence imaging and live cell monitoring showed each scaffold type was integrated into EVs either in membranes of the endocytic compartment, the plasma membrane, or both. Methods: Using a combination of gene fusion, molecular imaging, and immuno-based on-chip analysis, we examined the effects of various protein scaffolds, including endogenous tetraspanins (CD9, CD63, and CD81) and exogenous vesicular stomatitis virus glycoprotein (VSVG), on the efficiency of integration in EV membranes, the physicochemical properties of EVs, and EV uptake by recipient cells. ![]() ![]() ![]() In this study, we quantify the effects of genetic manipulations of different membrane scaffolds on the physicochemical properties, molecular profiles, and cell uptake of the EVs. These functions can be introduced to EVs by genetic manipulation of membrane protein scaffolds, although the efficiency of these manipulations and the impacts they have on the properties of EVs are for the most part unknown. Native EVs, however, usually do not interact specifically with target cells or harbor therapeutic drugs, which limits their potential for clinical applications. Background: Human cell-secreted extracellular vesicles (EVs) are versatile nanomaterials suitable for disease-targeted drug delivery and therapy.
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