The potential of exosomes in regenerative medicine and in the diagnosis and therapies of neurodegenerative diseases and cancer

Abstract

Exosomes, nanosized extracellular vesicles released by various cell types, are intensively studied for the diagnosis and treatment of cancer and neurodegenerative diseases, and they also display high usability in regenerative medicine. Emphasizing their diagnostic potential, exosomes serve as carriers of disease-specific biomarkers, enabling non-invasive early detection and personalized medicine. The cargo loading of exosomes with therapeutic agents presents an innovative strategy for targeted drug delivery, minimizing off-target effects and optimizing therapeutic interventions. In regenerative medicine, exosomes play a crucial role in intercellular communication, facilitating tissue regeneration through the transmission of bioactive molecules. While acknowledging existing challenges in standardization and scalability, ongoing research efforts aim to refine methodologies and address regulatory considerations. In summary, this review underscores the transformative potential of exosomes in reshaping the landscape of medical interventions, with a particular emphasis on cancer, neurodegenerative diseases, and regenerative medicine.

Keywords: biomarker; cancer; exosomes; neurodegenerative diseases; regenerative medicine.

Figure 1

Structure of exosomes. From a structural perspective, exosomes can be defined as lipid nanoparticles characterized by a phospholipid bilayer membrane. The exosomal membrane is enriched with a diverse array of proteins and saccharide markers, including immunomodulatory molecules, such as PD-1 and PD-L1, and hormone receptors, such as EGFR, tetraspanins, and glypicans. The internal composition of exosomes comprises a variety of biomolecules, including intracellular and cytoskeletal proteins, nucleic acids, growth factors, and cytokines. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 2

Biogenesis of exosomes. Extracellular membranes are characterized by the presence of numerous transmembrane proteins, including various receptors. (1) Upon ligand binding, receptor-mediated endocytosis is initiated, facilitated by actin filaments, which are integral components of the cytoskeleton. This process results in the invagination of the membrane surrounding the receptor, leading to the formation of an early endosome within the cell. (2) In this early endosome, the bilayer phospholipid membrane exhibits an orientation that is opposite to that of the cytoplasmic membrane, causing the extracellular domains of the transmembrane proteins to be directed inward, toward the lumen of the endosome. (3) Within the cellular context, endosomes are integral components of the complex endosomal-lysosomal system that interacts in a parallel manner (in both directions) with various organelles (e.g., Golgi apparatus and endoplasmic reticulum). This interaction allows endosomes and exosomes to encapsulate biomolecules derived from diverse cellular compartment. (4) During this process, early endosomes undergo maturation into late endosomes, which possess the normal orientation of transmembrane proteins and (5) generate intraluminal vesicles that will ultimately become exosomes. (6) Following the fusion of multi-vesicular bodies containing these intraluminal vesicles with the cytoplasmic membrane, exosomes are released into the extracellular environment. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 3

Distribution of exosome therapy and diagnostics concerning the target diseases (74). The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 4

Potential of exosomes in cancer diagnostics. The applicability of exosomes in cancer diagnostics is detailed in Supplementary Table S1. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 5

Potential of exosomes in the diagnosis of neurological diseases. In AD, protein markers such as total tau, phosphorylated T181-tau (p-T181-tau), phosphorylated S396-tau (p-S396-tau), and amyloid-beta 42 (Aβ42) derived from neural-derived blood exosomes are indicative of neurodegeneration and plaque formation. Notably, GAP43, SNAP25, and synaptotagmin 1 can be detected even in asymptomatic stages of AD. Furthermore, exosomal Aβ42, Aβ40, and P-T181-tau have been implicated in schizophrenia. In the context of PD and ALS, exosomal α-synuclein and neurofilament light chain exhibit promising potential as biomarkers for disease monitoring and progression. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 6

Exosomes represent a promising delivery system for the transport of anticancer agents. In murine cancer models, specifically in breast and ovarian carcinoma, exosomal formulations exhibit lower cardiotoxicity and higher efficacy compared to free doxorubicin. In the case of paclitaxel, exosomal formulations provide significantly improved intracellular delivery into 3LL-M27 cells (Lewis carcinoma expressing P-glycoprotein, which is associated with drug resistance) when compared to liposomal formulations and polystyrene nanoparticles. Furthermore, in these murine models, exosomes have been shown to suppress the development of metastases. Regarding natural agents, curcumin-loaded exosomes display promising efficacy against colon and pancreatic carcinomas, exhibiting antimetastatic effects and reduced inflammation. Exosomes are also suitable for the transport of biological agents such as microRNAs. For instance, exosomes loaded with miR-379 and miR-144-5p demonstrate potent effects against breast cancer and pancreatic ductal adenocarcinoma. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 7

Anti-tumor effects of T-cell-derived exosomes. Following activation by antigen-presenting cells (1), T cells generate exosomes containing PD-1 (2), which directly attenuate the immunosuppressive effects of cancer cells (4) by facilitating the degradation of PD-L1 (5) present on the surface of tumor cells. In addition, T-cell-derived exosomes (3) inhibit the functionality of immunosuppressive exosomes expressing PD-L1 (5), produced by cancer cells. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 8

Exosomes in the treatment of neurodegenerative diseases. Due to their ability to cross the BBB, exosomes are being investigated for the treatment of neurodegenerative diseases. In a rat model of PD, bone marrow-derived mesenchymal stem cell exosomes (MSCs-EXOs) have been shown to improve motor function. Similarly, MSCs-EXOs with a high content of sphingosine-1-phosphate have been found to decrease Aβ deposition and enhance cognitive function in a mouse model of AD. In a mouse model of schizophrenia, MSCs-EXOs have been reported to reduce cerebrospinal fluid glutamate levels and alleviate schizophrenia-related behaviors. Exosomes derived from murine microglial cells contain IL-4, an anti-inflammatory cytokine, and lactadherin, a phagocytic “eat me” signal, which reduce neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (a MS model). Similarly, effects were observed with macrophage-derived exosomes that were modified with derivatives of sialic acid, containing resveratrol. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.