Comparative Analysis of Different Origin-Derived Exosomes for Future Regenerative Endodontic Therapies: A Systematic...

Exosomes are gaining considerable attention as a cell-free approach for regenerative endodontic procedures, because they naturally regulate cell signaling and actively drive tissue healing. However, the regenerative potential of exosomes may vary by cellular origin, highlighting the need to evaluate source-dependent therapeutic applications.

This systematic review aimed to compare the regenerative potential of exosomes derived from different cellular sources and assess their biological effects, molecular mechanisms, and translational relevance for regenerative endodontic therapies.

A systematic review following PRISMA flow chart 2020 guidelines and a percentage summary of risk-of-bias assessment using the Modified SYRCLE Risk of Bias tool identified 216 eligible studies from PubMed, Web of Science, and Scopus, with 30 studies included in the final detailed synthesis.

Evidence consistently demonstrated that exosomes promote cell proliferation, migration, odontogenic differentiation, angiogenesis, and immunomodulation through signaling pathways including AKT, ERK, PI3K/AKT, Wnt/β-catenin, and TGF-β/SMAD. Exosomes derived from dental stem cells exhibited superior tissue-specific regenerative and odontogenic potential, making them particularly suitable for dental pulp regeneration. In contrast, exosomes from non-dental sources offered advantages in accessibility, scalability, and enhancement of early proliferative and angiogenic responses. Furthermore, engineered exosomes and advanced delivery platforms, including hydrogels and biomaterial-based scaffolds, improved therapeutic efficacy by enhancing cargo stability, retention, and targeted tissue regeneration.

Exosome-based therapies represent a promising strategy for regenerative endodontics, with therapeutic outcomes strongly influenced by exosome source. Endogenous sources, such as DPSC-derived exosomes, appear most suitable for pulp-dentin complex regeneration but are less practical than exogenous sources, such as PRP, WJMSC, and ADSVF exosomes, for scalable clinical applications. To reach the clinic, upcoming studies need to standardize exosome isolation and profiling, pinpoint specific clinical uses for each source, and incorporate modern delivery biomaterials.