An Immunomodulating Regenerating Hydrogel That Rescues the Oxidative Microenvironment and Reverses Cell Senescence for Osteoporotic Bone Defects

Osteoporosis, which is characterized by reduced bone mass and structurally compromised bone tissue, along with aberrant levels of reactive oxygen species (ROS) and inflammation, has been a pressing clinical challenge. A large accumulation of ROS and pro-inflammatory factors can result in mitochondrial dysfunction and progressive cellular senescence, impeding efficacious regeneration of bone defects. Herein, in this work, a ROS-responsive hydrogel system containing HA-PBA coated Ce-ZOL nanocomposites (GHCZ) for excessive ROS scavenging and reversal of cellular senescence to accelerate bone regeneration in osteoporosis was designed and presented. The GHCZ hydrogel system allows for the sustained release of HA-PBA coated Ce-ZOL nanoparticles, which may scavenge the extracellular and intracellular ROS of BMSCs and macrophages through their prominent enzyme-like catalytic effect. Moreover, the GHCZ hydrogel system transforms the polarization phenotype of macrophages into anti-inflammation M2 type and inhibits pro-inflammatory cytokines. Meanwhile, it could reverse the senescence of BMSCs and apparently elevate their pro-osteogenic capacity through safeguarding mitochondrial function and reprograming the metabolic processes, ultimately promoting the healing of bone defects. Based on <i>in vitro</i> and <i>in vivo</i> results, powerful immunomodulation, favorable pro-inflammatory/oxidative microenvironment reshaping properties, desirable mitochondrial protection, and superior pro-osteogenic capacity of such a GHCZ hydrogel system display the profound effects on augmenting bone repair, which offers a paradigm for treating osteoporotic bone defects.