Despite significant efforts made in this relatively new field of research, our understanding of exosomes remains limited by factors including inefficient separation methods, the lack of unique biomarkers, and the lack of high-resolution visualization techniques. Exosomes are small in size, which can effectively prevent the phagocytosis of mononuclear macrophages and freely cross the wall of blood vessels and the extracellular matrix. The expression of CD55 and CD59 on its surface prevents the activation of opsonin and coagulation factors, so it can be widely distributed and kept stable in biofluids. Compared to liposomes and other nanodelivery systems that are synthesized in vitro, exosomes originate in the body and, in theory, have better biocompatibility and lower immunogenicity.
In fact, due to the heterogeneity of exosomes, they carry several proteins on the surface, which enter cells in a variety of ways after coming into contact with cells. Among them, receptor-mediated endocytosis is one of the main forms of information communication between exosomes and target tissues, which optimizes the exosome endocytosis process and promotes the internalization of the encapsulated drug and facilitates the continuous and stable transport of the content in the blood with high transport efficiency. In addition, exosomes have a great capacity to locate target tissues or cells and penetrate biological barriers (such as the blood-brain barrier), so they have the advantage of natural drug delivery and are promising carriers of specific drugs, which can be used to deliver genetic drugs, traditional Chinese medicine, Western medicine, etc. 97,98 However, natural exosomes can have problems such as weak targeting and are likely to be rapidly eliminated in the body, resulting in a poor therapeutic effect.
At this time, they are usually modified to form designed exosomes. Genetically engineered exosomes refer to natural exosomes loaded with therapeutic or modified agents. In the next part, the applications of the targeted exosome delivery system will be explained, primarily from the perspective of drug loading and surface modification. The different loading strategies of exosomes not only increase loading efficiency, but they can also partially resolve the integrity and biological limitation of exosomes (Xu et al. Its low solubility, poor stability, rapid metabolism, short half-life and other defects lead to lower bioavailability, limiting its application in the treatment of diseases.
It is to be hoped that the current limitations in exosome studies will soon be resolved and confirm the role that exosomes play as messengers of intercellular signaling and as biomarkers of impending disease states. However, due to some limitations of antibodies, including their large size, complex structure, and induction of the immune response, simpler antibody fragments, such as single-domain antibodies (sdAbs) or single-chain variable fragments (scFv), have been widely used (Pham et al. Non-commercial uses of the work are allowed without any other permission from Dove Medical Press Limited, provided the work is duly attributed. Several bioengineering strategies could address the limited loading efficiency and impurity of exosomes (Weng et al.
Despite the significant advantages of liposomes, as the oldest and most studied drug delivery vehicle, their applications are restricted due to their limited stability, long-term safety, and activation of an acute hypersensitivity reaction (Sercombe et al. Therefore, genetically modified exosomes could be an effective approach to overcome existing limitations and expand their carrying capacity for desired therapeutic agents (Fu et al. However, storage stability, low yield, low purity and weak targeting of exosomes limit their clinical application. Current technologies for the analysis of exosome loads and their limitations will be analyzed, and solutions will be considered to improve them.
With a 3D culture, the limited surface area can be maximized to obtain exosome yield, but the resulting value is very different from the value of large scale production. By counteracting the immunosuppressive microenvironment of tumors by activating the immune response, tumor-derived exosomes can address the limitations of current immunotherapies (Perocheau et al. Although paclitaxel (PTX) is a widely used anti-tumor drug, which can play a therapeutic role in a variety of malignant tumors,35, it is a highly hydrophobic compound and has dose-dependent side and toxic effects, so its clinical application is limited. In addition, the short half-life index of circulating exosomes is one of the main limitations of this route of administration (Kučuk et al.
However, the use of PEGylation can address this limitation by preventing the rapid removal of exosomes from the circulation (Kučuk et al. The presence of the blood-brain barrier (BBB) limits the application of almost 98% of agents for the treatment of diseases of the central nervous system, and its clinical application is extremely difficult.
