Baicalein-manganese nanoparticles for antioxidant and osteogenic therapy of bone injury

Abstract

Oxidative stress is increasingly recognized as a key pathological driver of skeletal degeneration in diabetes, aging, trauma, and other orthopedic disorders, where excessive reactive oxygen species (ROS) compromise osteoblast and bone marrow mesenchymal stem cell (BMSC) function while promoting osteoclast activity. Natural polyphenols such as baicalein (BA) exhibit potent antioxidant effects but are hindered by poor solubility and limited stability. Here, we report a series of BA-X self-assembled nanoparticles, in which X represents osteogenic metal ions including Mg^2 + , Mn²⁺, Cu²⁺, Zn²⁺, and Sr²⁺. Among these, BA-Mn demonstrated the most robust radical-scavenging activity in DPPH, ABTS, and multiple ROS-targeted assays. BA-Mn exhibited nanoscale dimensions, uniform coordination, and excellent cytocompatibility, significantly reducing intracellular ROS and protecting H₂O₂-injured BMSCs. Functionally, BA-Mn restored osteogenic differentiation under oxidative stress, enhancing alkaline phosphatase activity, mineral deposition, and osteogenic gene expression. Transcriptomic analysis further revealed concurrent activation of cell cycle, PI3K-Akt, and MAPK signaling pathways, alongside suppression of ferroptosis and ROS-related carcinogenesis. Collectively, these findings establish BA-Mn as a multifunctional nanoplatform that integrates antioxidant defense with osteogenic stimulation, offering a promising therapeutic approach for oxidative stress-related bone disorders.