Extracellular vesicles efficiently deliver survival motor neuron protein to cells in culture

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene, leading to a low quantity of SMN protein in cells. This depletion of SMN protein preferentially leads to death of motor neurons and, consequently, muscle atrophy, in addition to defects in many other peripheral tissues. SMN protein is naturally loaded into extracellular vesicles (EVs), which are sub-micron-sized, membrane-bound particles released from all cell types. The innate ability of EVs to deliver cargo to recipient cells has caused these vesicles to gain interest as therapeutic delivery vehicles. In this study, we show that adenovirus-mediated overexpression of SMN protein in HepG2 cells leads to the release of EVs loaded with high levels of SMN protein into conditioned medium. Application of this medium to recipient cells in tissue culture led to uptake of the SMN protein, which subsequently transited to the nucleus and co-localized with Gemin2 protein, forming nuclear gem-like structures similar to the native SMN protein. Overall, this work demonstrates that SMN protein can be delivered to cells through EVs, which holds promise as a potential therapy for patients with SMA.