Modulating Macrophage Polarization via Core–Shell Nanofiber Membranes with Sequential Drug Delivery for Periodontal Regeneration

Periodontitis requires both inflammation suppression and bone regeneration, yet temporal coordination remains challenging. A core–shell nanofibrous membrane (ICA-PCL@ASTA-PLGA) was fabricated by coaxial electrospinning, with an astaxanthin (ASTA)-loaded poly(lactic-co-glycolic acid) (PLGA) shell and an icariin (ICA)-loaded polycaprolactone (PCL) core for sequential drug delivery. Differential degradation enabled rapid initial ASTA release and sustained ICA release over 8 weeks, providing early anti-inflammation followed by osteogenesis. This sequential release drove macrophage polarization from M1 to M2, downregulating proinflammatory and upregulating reparative factors. ASTA inhibited inflammation, while ICA promoted osteogenic gene expression and matrix mineralization, with temporally controlled synergy. These outcomes align with ASTA modulating NF-κB and ICA activating MAPK pathways, as previously reported. In a rabbit periodontitis model, the membrane significantly improved the immune microenvironment and alveolar bone regeneration, outperforming single-drug-loaded scaffolds. This material-guided sequential delivery strategy integrates immunomodulation and osteogenesis, highlighting “material-guided temporal pharmacology” as a paradigm for treating inflammatory tissue defects.