An osteoimmunomodulatory microneedle patch targeting ER-mitochondria calcium crosstalk for periodontal tissue regeneration.

Functional reconstruction of periodontal tissue defects remains a clinical challenge, primarily owing to sustained proinflammatory responses. Endoplasmic reticulum stress (ERS) and mitochondrial dysfunction have been identified as pivotal regulators driving macrophage proinflammatory activation, yet their pathological link remains unclear. In this study, transcriptomic analyses revealed that ERS and mitochondrial dysfunction were mutually reinforced via dysregulated intracellular Ca2+ transport. To target this mechanism, we designed dual-functional polydopamine nanoparticles (PDAB NPs) by leveraging the metal ion-chelating property of polydopamine to scavenge excessive Ca2+, while loading the osteogenic peptide bone morphogenetic protein 9 (BMP9) to confer pro-osteogenic activity. Considering the anatomical constraints of periodontal tissues that hinder nanotherapeutic delivery, we strategically constructed an osteoimmunomodulatory microneedle (OIMN) integrated with decellularized extracellular matrix (dECM) for localized PDAB NPs delivery. Results demonstrated that OIMN not only restored ERS and mitochondrial homeostasis, but also remodeled macrophage polarization, thereby mitigating periodontal inflammation. Moreover, the improved osteoimmune microenvironment further promoted the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) and accelerated periodontal bone regeneration. Collectively, this study presents a novel therapeutic strategy for periodontitis via regulating ER-mitochondrial Ca2+ crosstalk and establishes a translational paradigm for treating other inflammatory bone diseases.