In recent years, various drug nano-delivery platforms have emerged to enhance drug effectiveness in cancer treatment. However, their successful translation to clinics have been hampered by unwanted side effects, as well as associated toxicity. Therefore, there is an imperative need for drug delivery vehicles capable of surpassing cellular barriers and also efficiently transfer therapeutic payloads to tumor cells. Exosomes, a class of small extracellular vesicles naturally released from all cells, have been exploited as a favorable delivery vehicle due to their natural role in intracellular communication and biocompatibility.
In this review, researchers from the University of Minho discuss exosome biogenesis, contents, forms of isolation and their natural functions, further complemented with the various successful methodologies for therapeutic payloads encapsulation, including distinct loading approaches. In addition, grafting of molecules to improve pharmacokinetics, tumor homing-ligands, as well as stimuli-responsive elements to enhance cell specificity are also debated. In the end, the current status of clinical-grade exosome-based therapies is outlined.
Biogenesis and molecular composition of exosomes
A. The invagination of the plasma membrane forms a cup-shaped structure that includes cell-surface and soluble proteins associated with the extracellular environment, leading to the early sorting endosome formation. Early sorting endosome can mature into late sorting endosome and eventually generate intracellular multivesicular bodies (MVBs). MVBs form by inward invagination of the endosomal limiting membrane, resulting in MVBs comprising several intraluminal vesicles (ILVs) (future exosomes). MVBs can either fuse with autophagosomes or lysosomes to be degraded. MVBs that do not follow these paths can be transported to the plasma membrane and dock on plasma membrane. Exocytosis leads to the release of exosomes with similar lipid bilayer orientation as the plasma membrane. B. Exosome surface proteins include tetraspanins (CD63, CD81 and CD9), integrins, among others. Exosomes can contain different forms of cell surface proteins, signaling proteins, nucleic acids, amino acids, metabolites and proteins. Partially created with BioRender.com.