Hollow Mesoporous Polydopamine Nanocarriers Loaded With Curcumin Nanoparticles Modulate Macrophage Polarization and Support Osteogenic Differentiation: Association With Acat3/Fatty Acid Oxidation-Related Metabolic Changes.

Periodontitis is a chronic inflammatory disease driven by dysregulated host immune responses. Macrophages, as key innate immune cells, play important roles in periodontal inflammation and bone homeostasis, and M2-like macrophage polarization has been associated with improved osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Curcumin possesses anti-inflammatory and bone-protective properties, but its application is limited by poor aqueous solubility, chemical instability, and low bioavailability. In this study, curcumin nanoparticles (CUR NPs) were prepared by a reprecipitation/nanoprecipitation method and encapsulated into hollow mesoporous polydopamine (HMPDA) to construct HMPDA-CUR NPs. The resulting nanoparticles showed improved aqueous dispersibility, favorable biocompatibility, and sustained-release behavior. In vitro experiments showed that HMPDA-CUR NPs promoted the shift of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages from an M1-like pro-inflammatory phenotype toward an M2-like anti-inflammatory phenotype, with downregulation of M1-related markers and upregulation of M2-related markers. Conditioned medium from HMPDA-CUR NP-treated macrophages further enhanced osteogenic differentiation of BMSCs. Transcriptomic and RT-qPCR analyses showed that CUR NPs upregulated Acat3 and several fatty acid oxidation-related genes, indicating an association between CUR NP treatment and FAO-related metabolic remodeling. Direct FAO flux was not assessed in the present study. In a rat ligature-induced periodontitis model, HMPDA-CUR NPs showed a non-significant trend toward alleviating alveolar bone loss, indicating that the local delivery strategy requires further optimization. Overall, HMPDA-CUR NPs represent a promising immunomodulatory nanosystem for improving the periodontal bone-regenerative microenvironment, although additional mechanistic and delivery-optimization studies are required before translational application.