Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders.

Lysosomal storage disorders (LSDs) constitute a group of monogenic systemic diseases resulting from deficiencies in specific lysosomal enzymes that cause the intralysosomal accumulation of non- or partially degraded substrates, leading to lysosomal dysfunction. In some cases of LSDs, the bone is more severely affected, thus producing skeletal manifestations in patients. Current therapies, such as enzyme replacement therapy (ERT) and gene therapy (GT), show limited efficacy in correcting skeletal abnormalities. Increasing evidence suggests that microenvironmental disturbances also contribute significantly to disease pathogenesis. Therefore, therapeutic strategies targeting lysosomal dysfunction and microenvironmental dysregulation are needed. Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are emerging as promising candidates in regenerative medicine due to their immunomodulatory, pro-regenerative, and paracrine properties. MSC-EVs have shown potential to modulate the microenvironment and favor tissue repair in bone-related disorders such as osteoarthritis and osteoporosis. Interestingly, MSC-EVs can be engineered to reach the bone and carry therapeutics, including ERT- and GT-related molecules, enabling targeted delivery to hard-to-reach bone regions. This review describes the main features of MSC-EVs and discusses the therapeutic potential of MSC-EVs as a potential cell-free strategy for bone-affected LSDs.