Milk-derived exosomes (MDE) for photosensitizer delivery in photodynamic therapy: A review

Photodynamic therapy (PDT) is a novel light-based modality that relies on photoactivatable photosensitizers (PSs) to generate cytotoxic reactive oxygen species (ROS), but its clinical prospects are impeded by issues related to poor tumour specificity, penetration and off-target phototoxicity. Milk-derived exosomes (MDE), naturally occurring extracellular vesicles (30-150 nm in diameter) with excellent biocompatibility and low immunogenicity, have recently emerged as promising vehicles in drug delivery. MDE enhance intercellular communication by transporting proteins, lipids, and nucleic acids between cells. They have gained significant attention in recent years for their potential use in drug delivery, particularly for hydrophobic PSs, gene and protein delivery. MDE are of particular interest due to their abundance, ease of isolation, and biocompatibility. Herein we reviewed recent developments in MDE-mediated PDT, with a focus on three key areas: isolation and loading techniques, stimuli-responsive release and targeting such as pH-sensitive linkers or surface-anchored ligands (e.g., folic acid), therapeutic applications and in vivo efficacy. Several lines of evidence showed that MDE loaded with PSs significantly enhance tumour uptake and cause severe regression in vivo tumour models of glioblastoma and oral cancer, following systemic or oral administration. Overall findings from this review suggest that clinical translation depends on addressing key challenges related to scalable purification, reproducible drug loading and thorough safety profile screening. Therefore, it is essential for researchers to actively standardize manufacturing processes, conduct thorough in vivo validation, and investigate combination therapies with modalities for enhanced therapeutic efficacy.