Tri-modal nanocatalytic microenvironment regulations for macrophage reprogramming and osteoporotic fracture healing promotion.

The clinical challenge of osteoporotic fracture healing is rooted in a hostile local microenvironment characterized by oxidative stress, hypoxia, and acidosis, which stalls regeneration by trapping macrophages in a pro-inflammatory, metabolically crippled state. Herein, we report an intelligent nanocatalytic medicine composed of a pH-responsive calcium-aluminum layered double hydroxide (CaAl-LDH) decorated with a reactive oxygen species (ROS)-responsive manganese oxide (MnOx), denoted as CALM, for orthopedic implantation. This hierarchical system is designed to modulate key features of the "triple threat" microenvironment: the CaAl-LDH backbone dissolves in the local microenvironment to buffer the acidity, while the MnOx scavenges ROS and simultaneously generates therapeutic oxygen. This comprehensive microenvironment modulation supports mitochondrial function and drives the metabolic and phenotypic reprogramming of macrophages from a pro-inflammatory M1 to a pro-reparative M2 state. In a clinically relevant osteoporotic rat fracture model, the CALM coating significantly accelerated bone regeneration. Mechanistically, transcriptomic and protein-level analyses reveal that CALM exerts its immunomodulatory and osteogenic effects by activating the PI3K/Akt/GSK3β signaling pathway. This work presents a metabolically focused, nano-enabled strategy to break the cycle of non-union, offering a promising therapeutic platform for the treatment of osteoporotic fractures.