Vital pulp therapy aims to preserve pulp vitality by stimulating reparative processes. However, conventional approaches often result in incomplete tissue regeneration. Extracellular vesicles (EVs) have emerged as promising cell-free therapeutic agents because of their ability to regulate angiogenesis, odontogenesis, and immune responses through the transfer of bioactive molecules. Despite their significant regenerative potential, the clinical application of EVs remains limited by rapid clearance, insufficient local retention, and uncontrolled release following administration. To address these challenges, various extracellular matrix (ECM)-based and ECM-bioinspired scaffolds have been developed as delivery platforms. These scaffolds can provide structural support and enable controlled, localized release of EVs. This narrative review critically evaluates the current evidence regarding scaffold systems as EV delivery platforms for dental pulp regeneration, comparing their biological performance, methodological quality, and translational potential. Across the available studies, scaffold-assisted EV delivery consistently enhanced angiogenesis, odontogenic differentiation, mineralization, and immunomodulation; however, the evidence remains preclinical and is characterized by substantial heterogeneity regarding EV source, isolation and characterization methods, scaffold composition, experimental models, and outcome assessment. Current findings support the feasibility of scaffold-assisted EV delivery for regenerative endodontics, but important challenges remain, including standardization of EV production and characterization, scalable manufacturing, regulatory approval, and demonstration of long-term safety and functional pulp–dentin complex regeneration. Further well-designed translational and clinical studies will be essential before routine clinical implementation can be considered.

Background/Objectives: The objective of this study was to investigate the effects of local zoledronate treatment during periapical lesion development on inflammatory and bone remodeling responses in two immunologically distinct inbred rat strains, Dark Agouti (DA) and Albino Oxford (AO). Methods: Periapical lesions were induced in the mandibular first molars of AO and DA rats (n = 44) by pulp exposure. Animals were assigned to four groups: DA + zoledronate, DA + saline, AO + zoledronate, and AO + saline. Zoledronate (0.15 mg/kg) or saline was locally administered on days 0, 7, 14, and 21 during lesion development. Animals were sacrificed on day 28. Mandibles were analyzed radiographically and histologically for lesion size, while osteogenic activity was assessed by osteocalcin immunohistochemistry. Gene expression was evaluated by qRT-PCR, and systemic oxidative stress parameters were analyzed spectrophotometrically. Statistical analysis included parametric or non-parametric tests according to data distribution, with significance set at p < 0.05. Results: Zoledronate -treated AO rats exhibited smaller periapical lesions and higher radiographic grayscale density than DA rats (p < 0.05). Histological analysis confirmed the radiographic findings and demonstrated smaller lesion areas in AO rats. Osteocalcin expression was significantly higher in AO rats (p < 0.05), indicating increased osteogenic activity. At the molecular level, DA rats showed higher expression of TNF-α and IL-1β, whereas AO rats exhibited higher expression of IL-10 and IL-4 (p < 0.05). In addition, expression of osteoclastogenic factor RANKL was significantly lower in AO rats than in DA rats (p < 0.05), while OPG expression showed a non-significant tendency toward higher levels in AO rats. Systemic redox analysis demonstrated lower NO₂⁻ and O₂⁻ levels in zoledronate-treated AO rats, whereas no significant differences were observed in the remaining oxidative stress parameters. Conclusions: Following local zoledronate treatment during lesion development, Th2-dominant AO rats exhibited reduced inflammatory responses and increased osteogenic activity compared with Th1-dominant DA rats. In contrast, DA rats primarily demonstrated attenuation of osteoclastogenic signaling without comparable osteogenic responses. These findings indicate that the biological effects of local zoledronate treatment in developing periapical lesions are influenced by the host immune phenotype.