Tailored Extracellular Vesicles from Dental Stem Cells: Advances in Specific Modifications for Enhanced Therapeutic Applications

Abstract

Extracellular vesicles(EVs) derived from dental stem cells have emerged as a key focus in regenerative medicine, owing to their remarkable ability to promote tissue repair and regeneration. Recent advancements revealed that targeted modifications can significantly boost their functional properties, creating new possibilities for the regeneration field. This article provides an overview of the most recent progress in EVs derived from dental stem cells research, with a particular emphasis on diverse engineering strategies such as genetic, chemical, and physical techniques, and their role in enhancing therapeutic performance. Furthermore, the influence of these engineering methods on the yield of EVs is thoroughly examined, offering critical perspectives for improving large-scale manufacturing efficiency. Pretreatment-generated conditioned dental stem cells-derived EVs are also explored as an innovative approach, demonstrating superior biological functions and regenerative potential. By integrating contemporary findings, this review underscores the superior capabilities of modified EVs derived from dental stem cells in driving progress in regenerative medicine and lays the groundwork for future investigations focused on clinical applications and therapeutic innovation.

Keywords: extracellular vesicles; hypoxia; inflammation; preconditioning; predifferentiation; regeneration.

Figure 1

Preconditioning strategies and therapeutic applications of tailored extracellular vesicles. The schematic diagram reviews the therapeutic applications and pre-treatment strategies of dental stem cell-derived extracellular vesicles (EVs), which show significant potential in tissue recovery regeneration, anti-inflammation, and antioxidative effects. Key pre-treatment methods to enhance EVs efficacy include: 1. Hypoxia Preconditioning (via hypoxic culture or HIF-1α transfection) to boost pro-angiogenic and osteogenic potential. 2. Inflammatory Stimulation (using LPS, TNF-α, IFN-γ) to enhance immunomodulatory and pro-angiogenic properties. 3. Genetic Modification (via viral plasmid transfection or electroporation) to overexpress specific molecules and tailor EVs functions. 4. Pre-differentiation (using osteogenic/odontogenic medium) to improve osteogenic and odontogenic differentiation. 5. Apoptotic Induction (via staurosporine or serum starvation) to promote vascularization and tissue regeneration. Additionally, TWS119 pretreatment enhances EVs’ neurogenic potential, while high glucose exposure hinders periodontal regeneration. In summary, these strategies collectively optimize the therapeutic potential of dental stem cell-derived EVs for regenerative medicine applications. Created in BioRender. Liu, x. (2025) https://BioRender.com/v43r072.

Figure 2

Methods to increase the production of vesicles secreted by dental stem cells. This figure outlines the pre-treatment methods employed to enhance production in the field of extracellular vesicles derived from dental stem cells. These methods include hypoxia, inflammation, gene modification, and pre-differentiation, which mimic physiological conditions. Furthermore, mechanical techniques such as extrusion are utilized to produce more high-yield and uniformly sized vesicle-like structures(eNVs), while repeated freeze-thaw cycles facilitate the acquisition of high-yield novel internal vesicles(ACDVs). Created in BioRender. Liu, x. (2025) https://BioRender.com/e89g046.