Local H₂ release remodels senescence microenvironment for improved repair of injured bone

The senescence microenvironment, which causes persistent inflammation and loss of intrinsic regenerative abilities, is a main obstacle to effective tissue repair in elderly individuals. In this work, we find that local H₂ supply can remodel the senescence microenvironment by anti-inflammation and anti-senescence effects in various senescent cells from skeletally mature bone. We construct a H₂-releasing scaffold which can release high-dosage H₂ (911 mL/g, up to 1 week) by electrospraying polyhydroxyalkanoate-encapsulated CaSi₂ nanoparticles onto mesoporous bioactive glass. We demonstrate efficient remodeling of the microenvironment and enhanced repair of critical-size bone defects in an aged mouse model. Mechanistically, we reveal that local H₂ release alters the microenvironment from pro-inflammation to anti-inflammation by senescent macrophages repolarization and secretome change. We also show that H₂ alleviates the progression of aging/injury-superposed senescence, facilitates the recruitment of endogenous cells and the preservation of their regeneration capability, thereby creating a pro-regenerative microenvironment able to support bone defect regeneration.