Kaempferol-loaded mechanical-enhanced aerogel for augmenting osteoporotic bone regeneration

• An ECM-mimetic Gel/Alg-Kae aerogel was engineered to facilitate rapid host tissue integration and cell infiltration. • The Gel/Alg-Kae system enabled sustained release of hydrophobic kaempferol. • The Gel/Alg-Kae system endowed effective ROS scavenging and immune modulation functionality. • Gel/Alg-Kae aerogel promotes osteogenic and angiogenic differentiation, enhancing osteoporotic bone regeneration. In osteoporosis, bone defects are characterized by excessive reactive oxygen species (ROS) production, intensified inflammatory responses, accelerated stem cell senescence, and diminished regenerative potential in bone and vascular tissues, making them challenging to repair. This study introduces a Gel/Alg-Kae system, incorporating the antioxidant kaempferol, designed to foster a microenvironment that supports osteogenesis in osteoporotic bone defects. It provides an optimal material scaffold and mimics the natural extracellular matrix to expedite tissue penetration. The hydrophobic kaempferol within the aerogel enables prolonged release, efficiently neutralizing excess free radicals, reducing M1 macrophage polarization, and modulating the immune response. Additionally, the aerogel system promotes osteogenic and angiogenic differentiation. In vitro studies confirm that hydrogels significantly enhance osteoblastic differentiation of mesenchymal stem cells, deplete cellular ROS, regulate macrophage polarization, and alleviate inflammation. In vivo experiments using an osteoporosis defect model demonstrate the Gel/Alg-Kae system’s superior efficacy in bone and vascular regeneration. Consequently, the Gel/Alg-Kae system emerges as a viable drug delivery approach for the regeneration of osteoporotic bone.