A Novel Multifunctional VPA@ZIF-8 Nanocomposite Promotes Reparative Dentinogenesis in Pulpitis

In pulpitis treatment, vital pulp therapy (VPT) aims to preserve pulp vitality and promote dentin regeneration, yet conventional capping materials often lack reparative dentin inducing activity and fail to regulate local immune responses. In this study, valproic acid (VPA)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanocomposites (VPA@ ZIF-8 NPs) were developed to provide sustained therapeutic VPA release along with antibacterial and immunomodulation effects. Using a VPA-equivalent (VPA-eq) dosing strategy, we evaluated its antimicrobial, immunomodulatory, and reparative dentin inducing activity across multiple methods. In vitro studies showed that when treated with VPA@ZIF-8 NPs, stem cells from human exfoliated deciduous teeth (SHEDs) exhibited enhanced proliferation, migration, and mineralization ability, oral opportunistic pathogen V. parvula showed suppressed growth and biofilm formation activity, Further, macrophage polarization assays revealed that VPA@ZIF-8 NPs promoted the M2 polarization in THP-1 cells, indicated an anti-inflammatory function. Mechanistically, the classical odontogenic BMP2/SMAD1/RUNX2 pathway was activated by VPA@ZIF-8 NPs along with DSPP up-regulation in SHEDs. In vivo, local VPA@ZIF-8 NPs application recapitulated the macrophage M2 polarization and BMP2/SMAD1/RUNX2 pathway activation phenotype and contributed to marked reparative dentin bridge formation in an acute pulpitis rat model. In conclusion, this study demonstrated that the multifunctional VPA@ZIF-8 NPs integrated antibacterial, immunomodulatory, and regenerative induction effects, offering a novel and integrated therapeutic strategy for pulpitis.