Extracellular vesicles as carriers for protein and peptide therapeutics delivery: A review

Protein and peptide-based therapeutics hold immense potential for treating various diseases, including cancer, neurodegenerative disorders, and metabolic conditions. However, rapid degradation, poor bioavailability, short half-life, and early clearance limit their clinical application. Several protein and peptide modifications and drug delivery systems (DDS) tested including enzyme inhibitors, chemical modification and conventional nanoparticles have limitations like immune Reponses, extracellular vesicles (EVs), present a good solution to overcome this drawbacks. EVs have gained attention as novel delivery systems for protein and peptide therapeutics owing to their small size, biocompatibility, intrinsic targeting capabilities, lower immunogenicity, and ability to protect cargo from enzymatic degradation. EVs have demonstrated promising results in preclinical studies by enhancing the uptake, loading, penetration, and targeted release of protein/peptide cargos for conditions such as cancer, diabetes, and microbial infections. Additionally, they can serve as carriers for targeting peptides, enabling the delivery of synthetic drugs and genome-editing tools. This review explores the potential of EVs as drug delivery systems (DDS) for protein and peptide drugs, focusing on their advantages and characteristics, engineering and encapsulation, emerging EV and EV-cargo characterization techniques, release, and efficacy in overcoming the limitations of protein- and peptide-based delivery systems. The review also addresses challenges and future perspectives in translating EV-based protein and peptide delivery systems into clinical practice.