Polydopamine nanoparticles reprogram macrophage polarization via SERCA2-associated calcium remodeling to support osteogenic differentiation under inflammatory conditions.

Periodontitis is characterized by persistent immune-inflammatory responses and progressive alveolar bone loss, with macrophage polarization playing a pivotal role in shaping the local inflammatory microenvironment. Targeted immunopharmacological modulation of macrophage function, therefore, represents a promising strategy for controlling inflammation-associated tissue damage. Polydopamine (PDA), a multifunctional biomaterial with reported anti-inflammatory activity, has attracted increasing interest; however, the mechanisms underlying its immunomodulatory effects remain incompletely understood. In this study, we demonstrate that polydopamine nanoparticles (PDA NPs) effectively suppress lipopolysaccharide (LPS)-induced pro-inflammatory (M1) macrophage polarization while promoting an M2-like phenotype. Mechanistically, PDA NPs upregulate sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), enhance Ca2+ reuptake into the endoplasmic reticulum, and remodel intracellular calcium dynamics, thereby attenuating protein kinase R-like endoplasmic reticulum kinase (PERK)-mediated signaling and alleviating endoplasmic reticulum stress . Pharmacological inhibition of SERCA activity markedly reduces the regulatory effects of PDA NPs on calcium remodeling and macrophage polarization, indicating that SERCA2-associated calcium signaling contributes to PDA-induced immunomodulation. Functionally, PDA NPs-reprogrammed macrophages remodel the inflammatory paracrine environment and indirectly enhance the osteogenic differentiation of human periodontal ligament stem cells under inflammatory conditions in vitro. Collectively, these findings suggest that SERCA2-mediated calcium remodeling represents a potential immunopharmacological mechanism linking PDA nanoparticles to macrophage reprogramming. Moreover, the findings underscore the potential of PDA nanoparticles to simultaneously modulate inflammation and support osteogenesis in periodontal disease.