Zein-Ceria Hybrid Microparticles Enable Long-Term ROS-Scavenging Oxygenation for Osteogenic Microtissues Engineering

Oxygen- and biological cue-deprived microenvironments formed during tissue regeneration severely limit cell survival and differentiation, resulting in long-term structural and functional deficits. However, conventional oxygen-releasing biomaterials often exhibit burst releases, with the vast majority of oxygen released during the first few days, which is associated with high levels of concomitant reactive oxygen species (ROS)-derived oxidative stress and a lack of bioactive factors. Here, we report a hierarchically engineered zein-ceria hybrid microparticle that enables sustained ROS-neutral oxygenation for over 40 days and supplies an osteoinductive factor. A hydrophobic zein core stabilizes the oxygen source and suppresses burst release, while a ceria nanozyme-integrated shell continuously scavenges excess ROS via redox cycling. Biocompatible surface engineering enables the seamless integration of these microparticles within stem cell spheroids, which markedly enhances cell survival under anoxia. Their biofunctional surface supports enzymatic protein immobilization under physiological conditions, enabling spontaneous osteogenesis of engineered bone microtissues. In a severely oxygen-deprived mouse calvarial defect model, the engineered microtissues accelerated bone regeneration. Our biomaterial design enables control of burst oxygen release, ROS modulation, and growth factor release, built on a zein-ceria double-layer architecture, offering a modular platform that broadens the utility of oxygenating and bioactive micromaterials in regenerative medicine.