## 5 Pharmacologic Impact of Exosomes on the Treatment of Metabolic Diseases
### Exosome-Based Therapy: Between Promises and Limitations  
Exosome based therapies can be envisioned in the near to mid future due to the benefits of a suitable environment for cargo molecule preservation and specific organ or cell type specificity. An increasing number of strategies are being identified to regulate the mechanisms of exosome action and, potentially, to modulate their content to optimize intercellular communication. This represents a new frontier in pharmaceutical development. The discussed pathological effects and benefits of different exosome cargo has spurred the search for mechanisms to either inhibit cargo loading, delivery, and in situ effects or induce the production of some exosome classes. Technical challenges remain nonetheless. The understanding of inter-organ communication through exosomes has opened new therapeutic strategies, including methods to prevent exosome binding to target tissues or inhibit the expression of their cargo molecules [108]. For instance, nanoparticles or antagonismRs have been used to block the entry or to suppress the expression of miRNAs with metabolism-altering and tumor-promoting effects, such as miR-34a and miR-29a [109]. To inhibit the interaction between exosomes and their target tissues, thereby preventing the delivery of pro-inflammatory or pathological cargo, are being developed [93; 110]. AntagononiRs have been shown to effectively restore insulin sensitivity, indicating their potential for developing targeted therapies for metabolic diseases [93; 110]. Integrins on the exosomal membrane, which are vital for guiding exosomes to their target tissues [111]. Given this critical role, integrins such as \(\alpha\
u\beta 5\), have been targeted using monoclonal antibodies and antagonist peptides. By blocking integrin-mediated tropism, it is possible to modulate the tissue-specific effects of exosomes, particularly in conditions such as metabolic diseases, wherein exosome-driven signaling plays a critical role. Such strategies represent a promising avenue for therapeutic intervention. Conversely, exosomes designed with specific integrins could be engineered to carry therapeutic cargo molecules for targeted delivery to specific tissues. There are reports of exosome-based treatments, including the pilot study conducted by Paicius et al. in 2023. In this study, extracted exosomes from bone marrow mesenchymal stem cells were administered to 10 patients with refractory complex regional pain syndrome (CRPS). Exosome-treated patients showed a 50% reduction in pain after 6 months, additionally, there was an increase in grip strength and overall functionality in these patients [90; 112]. Exosomes from mesenchymal stem cells, rich in microRNAs and cytokines, demonstrate significant anti-inflammatory properties. They can be used to treat diseases with high inflammatory components, like COVID-19 and acute lung injury [94; 113]. For example, a study involving 24 patients with a positive PCR test for SARS-CoV-2 reported that administration of ExoFlo in a single dose led to a 71% recovery rate, with 13% of patients remaining critically ill and 4% dying from causes unrelated to the treatment. A 193% increase in the PaO2/FiO2 ratio was observed, with a \(p\)-value of <0.001 [95; 114], which translates into an improvement in pulmonary oxygenation. Recent studies have turned their attention to the critical task of reducing the expression of proteins that play a pivotal role in tumor development. One example is the CD47 protein, which is overexpressed in many cancers and correlates with dysfunctional macrophages and dendritic cells, indicating poor survival. Vesicles created with signal regulatory protein alpha (SIRP\(\alpha\)) can lower CD47 levels, increase IFN-\(\gamma\) secretion, and promote the infiltration of CD8+ and CD4+ T cells, helping to suppress tumor growth [113; 115]. Other therapeutic applications have been identified in the field of ocular diseases. Exosomes have been detected in various parts of the eye, including the retina, aqueous humor, vitreous body, and tears.