Reactive Oxygen Species-Regulating Nanoengineered Hydrogels for Bone Regeneration: A Mechanism-Based Framework of...

Bone regeneration is frequently impaired by excessive reactive oxygen species (ROS). Persistent oxidative stress disrupts mitochondrial function, sustains inflammation, and suppresses osteogenic differentiation. Nanoengineered hydrogels provide versatile platforms for local microenvironment remodeling. This review summarizes recent advances in ROS-regulating nanoengineered hydrogels for bone regeneration, with emphasis on redox microenvironment remodeling and osteoimmunomodulation. ROS-responsive hydrogels exploit pathological oxidants as endogenous triggers for on-demand release of small molecules, proteins, neuropeptides, ions, and nanocomposites. Intrinsic ROS-scavenging hydrogels directly attenuate oxidative injury through redox-active polymers, polyphenols, nanomaterials, metal-ion chelation, and oxygen-regulating components. Nanozyme-integrated hydrogels provide catalytic functions that regulate superoxide, hydrogen peroxide, glucose metabolism, oxygen availability, and mitochondrial oxidative stress. ROS-regulated osteoimmunomodulatory hydrogels reshape immune-bone crosstalk by promoting pro-regenerative macrophage functions, suppressing excessive osteoclastogenesis, controlling infection-associated inflammation, and enhancing angiogenic and osteogenic signaling. Remaining challenges include defining disease-specific therapeutic redox windows, establishing standardized mechanistic and safety assessments, and improving long-term nanoengineered-component biocompatibility. Future development of personalized hydrogel systems may accelerate translation toward precision bone-regenerative therapy.