BACKGROUND: Exosomes, nano-sized extracellular vesicles, have emerged as a promising tool for the diagnosis and treatment of various intractable diseases, including chronic wounds and cancers. As our understanding of exosomes continues to grow, their potential as a powerful therapeutic modality in medicine is also expanding. This systematic review aims to examine the progress of exosome-based clinical trials and provide a comprehensive overview of the therapeutic perspectives of exosomes. METHODS: This systematic review strictly follows PRISMA guidelines and has been registered in PROSPERO, the International Prospective Register of Systematic Reviews. It encompasses articles from January 2000 to January 2023, sourced from bibliographic databases, with targeted search terms targeting exosome applications in clinical trials. During the screening process, strict inclusion and exclusion criteria were applied, including a focus on clinical trials utilizing different cell-derived exosomes for therapeutic purposes. RESULTS: Among the 522 publications initially identified, only 10 studies met the stringent eligibility criteria after meticulous screening. The selection process involved systematically excluding duplicates and irrelevant articles to provide a transparent overview. CONCLUSION: According to our systematic review, exosomes have promising applications in a variety of medical fields, including cell-free therapies and drug delivery systems for treating a variety of diseases, especially cancers and chronic wounds. To ensure safety, potency, and broader clinical applications, further optimization of exosome extraction, loading, targeting, and administration is necessary. While cell-based therapeutics are increasingly utilizing exosomes, this field is still in its infancy, and ongoing clinical trials will provide valuable insights into the clinical utility of exosomes.