Multifunctional antibacterial-anti-inflammatory-osteogenic performance of ZIF-8/PDA composite scaffold for osteoporotic bone regeneration via intelligent quercetin delivery

To address the dual challenges of controlled drug delivery and microenvironment modulation in repairing osteoporotic bone defects, we developed a multifunctional poly(l-lactic acid) (PLLA)-based composite fibrous scaffold (PLLA/PDA/ZIF-8@Qu). The scaffold was fabricated via electrospinning, followed by in situ polydopamine (PDA) polymerization to robustly immobilize ZIF-8 nanocarriers loaded with quercetin (Qu) on the fiber surface. The mussel-inspired PDA coating served as an adhesive interlayer between ZIF-8 and PLLA. Additionally, it provided near-infrared (NIR) responsiveness and surface functionalization capability. Under osteoporotic acidic conditions (pH 5.0–6.0), the scaffold exhibited pH-triggered release behavior, ZIF-8 degradation accelerated Zn 2+ release, and cumulative Qu release reached 90 %. Zn 2+ contributed to antibacterial activity, while the PDA coating enabled NIR-driven photothermal/photodynamic synergy, achieving 100 % inhibition against both E. coliand S. aureus. Quercetin (Qu) exerted antioxidant effects via the Nrf2/ARE pathway and promoted macrophage polarization toward the M2 phenotype, thereby ameliorating the local inflammatory microenvironment. In vitro , the scaffold enhanced osteogenic differentiation of bone marrow mesenchymal stem cells, as indicated by a 2.3-fold increase in alkaline phosphatase activity, a 1.85-fold increase in mineralized nodule formation, and upregulated Runx2 expression. In a rat femoral defect model, the scaffold group at 8 weeks post-implantation showed increased bone mineral density (BMD) from 0.454 to 0.935 g/cm 3 and trabecular number (Tb.N) from 0.694 to 0.923 mm −1 , with the defect largely filled by newly formed bone. Collectively, these results demonstrate that the PDA-enabled, ZIF-8/Qu-integrated PLLA scaffold couples pH-responsive release with antibacterial, anti-inflammatory, and pro-osteogenic functions, supporting its potential as a bone repair material responsive to pathological microenvironments.