Valproic Acid-Loaded ZIF-8 Nanoparticles with Antibacterial, Immunomodulatory, and Dentin Regenerative Functions for Pulpitis Therapy

In pulpitis treatment, vital pulp therapy (VPT) aims to preserve pulp vitality and promote dentin regeneration. However, conventional pulp-capping materials usually lack reparative dentin-inducing activity and fail to regulate the local immune microenvironment effectively. In this work, valproic acid (VPA)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanocomposites (VPA@ ZIF-8 NPs) were designed to achieve high VPA loading capacity, excellent encapsulation efficiency, and sustained and pH-responsive VPA release kinetics. Using a VPA-equivalent (VPA-eq) dosing strategy, we systematically evaluated its biocompatibility, antimicrobial properties, immunomodulatory effects, and dentin-regenerative potential 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, and oral opportunistic pathogens Veillonella parvula and Streptococcus mutans showed suppressed growth and biofilm formation activities. Further, macrophage polarization assays revealed that VPA@ZIF-8 NPs promoted the M2-like polarization in THP-1 cells, indicating an anti-inflammatory function. Notably, the BMP2/SMAD1/RUNX2 pathway was activated by VPA@ZIF-8 NPs in the SHEDs. In vivo, local VPA@ZIF-8 NP application recapitulated the macrophage M2-like polarization and BMP2/SMAD1/RUNX2 pathway activation phenotype and contributed to marked reparative dentin bridge formation in a pulp exposure rat model. In summary, the multifunctional VPA@ZIF-8 NPs integrate biosafety, antibacterial, immunomodulatory, and dentin-regenerative-inducing capabilities, providing a promising and integrated strategy for vital pulp therapy against pulpitis.