ZnCe-LDO Nanozyme-Based Multifunctional Hydrogel Promotes Bone Regeneration by Inflammatory Macrophage Reprogramming and Piezo1 Activation

Prolonged or excessive inflammation may lead to impaired vascularization and bone regeneration, hindering the normal repair process of bone tissue. Although the regulation of inflammation is crucial for promoting a conducive microenvironment for bone regeneration, individual anti-inflammatory interventions frequently are inadequate in facilitating effective bone repair. Here, a multifunctional hydrogel (GelMA-ZC-Yoda1) with multifaceted therapeutic strategy was designed by integrating Zinc/Cerium-layered double oxide nanozyme (ZnCe-LDO, with catalase-like activity) and Yoda1 (an activator of the mechanically sensitive Piezo1 ion channel) into photocurable GelMA hydrogel. The ZnCe-LDO nanozyme in the hydrogel promoted M2 macrophage polarization by reprogramming inflammatory macrophages, establishing a favorable microenvironment, while the sustained release of zinc and cerium ions facilitated osteo/angiogenesis. Additionally, the Yoda1 released from the hydrogel chemically simulated a mechanical signal to activate the Piezo1 channel, regulating osteo/angiogenesis via the Piezo1/YAP1 signaling pathway. <i>In vivo</i> findings indicated that the GelMA-ZC-Yoda1 hydrogel application improved the inflammatory microenvironment and effectively enhanced osteo/angiogenesis in a rat calvaria defect model. This study supports the advancement of injectable hydrogels with multifunction, including inflammatory macrophage reprogramming and promotion of osteo/angiogenesis.