pH-Responsive 7,8-DHF/HZIF-8@PLGA microspheres for modulating the osteoporotic microenvironment: Osteogenesis, immunomodulation, and ROS scavenging.

Osteoporosis is a multifactorial skeletal disorder driven by impaired osteogenesis, chronic inflammation, and oxidative stress within an acidic bone microenvironment. To address this complex pathology, we developed an intelligent, pH-responsive drug delivery system comprising 7,8-dihydroxyflavone (7,8-DHF)/hollow zeolitic imidazolate framework-8 (HZIF-8) encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (7,8-DHF/HZIF-8@PLGA). This hierarchical platform integrates three therapeutic modalities: (i) 7,8-DHF activates the TrkB/Wnt/β-catenin pathway to promote osteoblast differentiation; (ii) Zn²⁺ released from HZIF-8 enhances osteogenesis and drives M2 macrophage polarization; and (iii) tannic acid (TA), used to construct the hollow structure, scavenges reactive oxygen species (ROS) and suppresses pro-inflammatory signaling. The system exhibits sustained, pH-triggered release over 20 days, with significantly accelerated payload release under acidic conditions (pH 5.5) that mimic the osteoclastic resorption lacunae. In vitro, 7,8-DHF/HZIF-8@PLGA rescues osteoblasts from acid-induced apoptosis, significantly upregulates alkaline phosphatase activity and osteogenic gene expression, and reprograms macrophages toward an anti-inflammatory phenotype. Furthermore, it demonstrates robust ROS-scavenging capacity, effectively mitigating oxidative damage. By simultaneously targeting osteogenesis, inflammation, and redox imbalance in a microenvironment-responsive manner, this multifunctional platform represents a promising strategy for the precision therapy of osteoporosis and other metabolic bone diseases.