Extracellular vesicles for delivery of functional telomerase.

BACKGROUND: Telomerase, essential for maintaining chromosomal telomere integrity and preventing cellular senescence, represents a promising therapeutic target. However, the inherent risks associated with existing treatments for telomerase deficiency-related diseases necessitate the development of safe and precise targeted delivery systems capable of reaching specific cell populations. Extracellular vesicles (EVs), nanoscale membrane-bound particles naturally secreted by cells, mediate intercellular communication by transporting bioactive molecules, including proteins and nucleic acids. We hypothesized that EVs could function as intrinsic vehicles for telomerase delivery. METHODS: To investigate this, we demonstrated the effective encapsulation of functional telomerase components, specifically TERT and TERC, within EVs. Furthermore, we observed that enhanced TERT expression led to increased telomerase activity within the EVs, as confirmed by TRAP assay results. RESULTS: These telomerase-loaded EVs, leveraging their inherent targeting capabilities and unique vesicular structure, efficiently delivered the active enzyme to recipient cells. In aged mice, delivery of telomerase via EVs restored endogenous telomerase activity, preserved telomere integrity, and attenuated senescence across multiple tissues. We observed that the internalized telomerase modulated the expression of senescence-associated markers, thereby delaying cellular aging and promoting cellular proliferation. CONCLUSIONS: These findings support the feasibility of EV-mediated intercellular telomerase delivery, suggesting a potential avenue for developing therapeutic interventions for pathologies associated with telomerase deficiency.