Extracellular vesicles (EVs) are small membrane-bound particles released by cells that can be taken up by recipient cells. Despite their discovery decades ago, their role in cell-to-cell communication has only recently been recognized. EVs carry nucleic acids and proteins that can influence the phenotype of recipient cells. For this to occur, EVs must fuse with target cell membranes, either directly or via endocytic uptake. EVs are of therapeutic interest as they are deregulated in diseases like cancer and can deliver drugs to target cells. Understanding the molecular mechanisms of EV uptake is crucial. EVs are taken up by various endocytic pathways, including clathrin-dependent endocytosis, caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. The uptake mechanism depends on proteins and glycoproteins on both the EV and target cell surfaces. Research indicates that EVs may enter cells through multiple routes, and the precise rules governing this process are still being explored. Protein interactions, such as those involving tetraspanins, integrins, and immunoglobulins, play a key role in EV uptake. Tetraspanins like CD63, CD9, and CD81 are enriched in EVs and facilitate their uptake. Integrins and immunoglobulins also contribute to EV internalization. Proteoglycans and glycoproteins are involved in EV uptake, with heparan sulfate proteoglycans playing a significant role. Lectins, such as DC-SIGN and DEC-205, also mediate EV uptake by recognizing specific ligands on EV surfaces. Endocytosis is the primary mechanism for EV uptake, involving processes like clathrin-mediated endocytosis, caveolin-dependent endocytosis, macropinocytosis, and phagocytosis. These processes are influenced by factors such as cholesterol, lipid rafts, and specific protein interactions. EV uptake is energy-dependent and requires a functional cytoskeleton. Inhibitors of these pathways have been used to study EV uptake, but their effects can be complex due to potential off-target effects. Lipid rafts, which are microdomains in the plasma membrane, are involved in EV uptake. They are rich in cholesterol and sphingolipids and can facilitate EV internalization. However, the exact role of lipid rafts in EV uptake is still under investigation. Cell surface membrane fusion is another possible entry mechanism, where EV membranes directly fuse with the plasma membrane. This process involves the merging of lipid bilayers and is facilitated by proteins like SNAREs, Rab proteins, and SM-proteins. EV uptake is cell-type specific, with some EVs being internalized more efficiently by certain cell types. The interaction between EVs and target cells depends on the presence of specific ligands and receptors. Understanding the mechanisms of EV uptake is crucialExtracellular vesicles (EVs) are small membrane-bound particles released by cells that can be taken up by recipient cells. Despite their discovery decades ago, their role in cell-to-cell communication has only recently been recognized. EVs carry nucleic acids and proteins that can influence the phenotype of recipient cells. For this to occur, EVs must fuse with target cell membranes, either directly or via endocytic uptake. EVs are of therapeutic interest as they are deregulated in diseases like cancer and can deliver drugs to target cells. Understanding the molecular mechanisms of EV uptake is crucial. EVs are taken up by various endocytic pathways, including clathrin-dependent endocytosis, caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. The uptake mechanism depends on proteins and glycoproteins on both the EV and target cell surfaces. Research indicates that EVs may enter cells through multiple routes, and the precise rules governing this process are still being explored. Protein interactions, such as those involving tetraspanins, integrins, and immunoglobulins, play a key role in EV uptake. Tetraspanins like CD63, CD9, and CD81 are enriched in EVs and facilitate their uptake. Integrins and immunoglobulins also contribute to EV internalization. Proteoglycans and glycoproteins are involved in EV uptake, with heparan sulfate proteoglycans playing a significant role. Lectins, such as DC-SIGN and DEC-205, also mediate EV uptake by recognizing specific ligands on EV surfaces. Endocytosis is the primary mechanism for EV uptake, involving processes like clathrin-mediated endocytosis, caveolin-dependent endocytosis, macropinocytosis, and phagocytosis. These processes are influenced by factors such as cholesterol, lipid rafts, and specific protein interactions. EV uptake is energy-dependent and requires a functional cytoskeleton. Inhibitors of these pathways have been used to study EV uptake, but their effects can be complex due to potential off-target effects. Lipid rafts, which are microdomains in the plasma membrane, are involved in EV uptake. They are rich in cholesterol and sphingolipids and can facilitate EV internalization. However, the exact role of lipid rafts in EV uptake is still under investigation. Cell surface membrane fusion is another possible entry mechanism, where EV membranes directly fuse with the plasma membrane. This process involves the merging of lipid bilayers and is facilitated by proteins like SNAREs, Rab proteins, and SM-proteins. EV uptake is cell-type specific, with some EVs being internalized more efficiently by certain cell types. The interaction between EVs and target cells depends on the presence of specific ligands and receptors. Understanding the mechanisms of EV uptake is crucial