A chrono-modulated oxygen-cycling scaffold reprograms immunometabolism to drive bone regeneration

Bone regeneration is governed by a tightly regulated oxygen rhythm that orchestrates the sequential phases of inflammation, repair, and remodeling. Early hypoxia promotes angiogenic sprouting, whereas subsequent reoxygenation favors vessel maturation and bone matrix deposition. Here, we engineered a near-infrared (NIR)-responsive composite scaffold, UCNP-Cy/CA@CCB, that operationalizes stage-specific oxygen control in vivo. A decellularized, calcined bovine cancellous bone (CCB) scaffold was prepared and subsequently coated with calcium alginate to obtain a calcium alginate-coated CCB (CA@CCB), which provides osteoconductive, bone-mimetic support. Within this scaffold, a module of upconversion nanoparticle (UCNP)-enabled cyanobacteria (Cy) was embedded to program local O₂ dynamics. With NIR off during the early phase, Cy respiration consumes O₂ to establish a reparative hypoxic window. At intermediate and late stages, NIR on activates Cy photosynthesis to release O₂ on demand, transitioning the milieu from hypoxia to reoxygenation, stabilizing neovasculature, and advancing osteogenesis. In a rat critical-sized defect model, this scaffold increased bone volume fraction (BV/TV) by more than 200% compared with controls and achieved early bridging by week 4. By operationalizing stage-specific oxygen control, this platform provides mechanistic insight into oxygen-related disease therapy and guides the design of next-generation oxygen-rhythm biomaterials.