## 5 Pharmacologic Impact of Exosomes on the Treatment of Metabolic Diseases
### Exosome-Based Therapy: Between Promises and Limitations
Research into alternative methods of intraocular drug delivery has opened new possibilities for using extracellular vesicles in the treatment of retinal diseases [116]. In addition, a recent report suggests using exosomes as biomarkers for early diagnosis of inflammatory bowel disease (IBD), with the potential for exosome-based strategies to be utilized therapeutically [96; 117]. On the other hand, exosomes have emerged as potential therapeutic agents in metabolic diseases due to their interaction with the receptor for advanced glycation end products (RAGE) that contributes to metabolic inflammation, insulin resistance, and endothelial dysfunction. Targeting exosome-RAGE interactions using monoclonal antibodies or receptor antagonists could mitigate these effects [118]. Advances in nanotechnology are increasing the potential of exosome-based therapies for different diseases. Mixed cargo exosomes have recently been used in a collagen-induced-arthritis (CIA) mouse model. CIA mice treated with M2-derived exosomes loaded with copper sulfide nanoparticles, along with rapamycin, and citrullinated multi-epitope antigen showed reduced cartilage lesions, decreased inflammatory cytokines, and increased anti-inflammatory cytokines [119]. This effect was attributed to the targeting of the mixed cargo exosomes to activated T cells, leading to copper nanoparticle-induced cuprotopsis [119]. Another recent example of nanoparticle-loaded mixed exosomes comes from iron loaded exosomes. DNA-containing exosomes obtained from 4T1 cells treated with 7-ethyl-10-hydroxycampttothecin (SN38) have been engineered to contain hollow mesoporous organosilica-encapsulated zero valent iron [120]. These exosomes target TNBC cells in a mice model and induce a specific ferprotosis effect in the mildly acidic tumor microenvironment [120]. Exosome-based therapies used along immunotherapy have recently proven promising against melanoma. \(\gamma\)\(\delta\)T-T cell-derived exosomes mixed with liposomes containing the FDA approved photosensitizer chlorine e6 target melanoma A375 cells and A375 tumors in nude mice in vivo and sensitize them to photodynamic therapy (PDT) through an ROS-dependent mechanism [121]. Tumor cells can survive immune therapy through loss or silencing of the stimulator of interferon genes (STING) protein [122], which can activate NF-\(\kappa\)B and IRF3 pathways, leading to cytokine production [116]. Recently, a strategy to activate this pathway in tumor cells and sensitize them to immunotherapy was developed. Tumor cell-derived exosomes were loaded with cyclic dinucleotides, which activate STING [123], conjugated with the synthetic triacylated lipopeptide, Pam3 CSK4, to increase their lipophilicity [123]. These exosomes proved effective in the sensitization of melanoma B16-OVA cells against antigen presenting cells (APCs) in vitro and in an in vivo mice model, improving survival rates [124]. These findings highlight the great potential exosome based therapy has when used with other available tools to generate more specific and effective therapies against the major diseases we currently face. Over recent years, evidence of the therapeutic potential for the treatment of several diseases with plant-derived exosomes has accumulated. In many cases, plant exosomes are loaded with cargo such as modified nanoparticles or chemotherapeutic drugs. Specifically, citrus-derived EVs have proven stable carriers of doxorubicin against HeLa cells [125]. In another recent example of promising results of the use of plant exosomes, ginger-derived exosomes loaded with hollow mesoporous silica nanoparticle-encapsulated hydrogen nano-generators were used in T2 DM model mice [126]. These hydrogen-producing exosomes lead to islet \(\beta\)-cell dedifferentiation, increased pancreatic \(\beta\)-cell proportions, and microbiota modulation [127]. Strikingly, plant-derived exosomes can also exert positive therapeutic effects through their own cargo molecules.