Engineering Extracellular Vesicle Production Through Magnetic Ion Channel Activation for Bone Regeneration

Bone disorders represent a significant global health challenge. Extracellular Vesicles (EVs) are emerging as a promising nanotherapeutic approach for bone regeneration, addressing the translation barriers associated with cell-based therapies. Despite their immense potential, the clinical application of EVs is limited by low production yields and inconsistent quality. Magnetic Ion Channel Activation (MICA) leverages remote magnetic fields to stimulate mechano-sensitive ion channels through magnetic nanoparticles (MNPs). This study explores the potential of utilising MICA to enhance the production yield and therapeutic efficacy of EVs for bone regeneration. The findings demonstrate that MICA significantly increased the production yield of EVs from MC3T3 pre-osteoblasts compared to magnetic stimulation or TREK1 functionalised graphene oxide- -GOMNP particles alone. The obtained EVs exhibited typical size distribution, morphology, and EV protein expression, consistent with nano-sized vesicles. Furthermore, MICA/TREK EVs treatment considerably enhanced human bone marrow-derived mesenchymal stem cells (hBMSCs) osteogenic differentiation and mineralization compared to EVs derived from MICA, TREK, or untreated groups. Proteomics analysis revealed the enrichment of proteins involved in mechanotransduction and osteogenic differentiation within MICA/TREK EVs. In summary, these findings highlight the substantial potential of MICA as a platform to enhance the scalable production and therapeutic application of pro-regenerative EVs for bone augmentation strategies.