Layered double hydroxide-based ROS-scavenging nanozyme hydrogels re-establish osteoimmune-angiogenic coupling for osteoporotic bone repair

Abstract Background Osteoporotic bone defects (OP-BDs) present a significant clinical challenge because of a pathological microenvironment characterized by severe oxidative stress, persistent inflammation, and disrupted metabolic coupling between osteoblasts and osteoclasts. To overcome these barriers, we developed a microenvironment-remodeling nanocomposite hydrogel for re-establishing osteoimmunological and angiogenic homeostasis. Results Manganese dioxide (MnO 2 ) nanozymes were first deposited onto layered double hydroxides (LDHs) via an in situ redox reaction to fabricate MnO 2 @LDHs nanocomposites, which were subsequently integrated into a gelatin methacryloyl (GelMA) network through interfacial hydrogen bonding to form the final hydrogel (MnO 2 @LDHs/GelMA). In vitro assays confirmed that the MnO 2 coating exhibited catalase-like activity, decomposing pathological hydrogen peroxide (H 2 O 2 ) into water and oxygen (O 2 ), thereby alleviating oxidative stress and protecting the LDH framework from acid-induced degradation. The resulting ROS depletion modulated macrophage polarization toward a pro-regenerative phenotype, thereby attenuating the inflammatory microenvironment and promoting endothelial cell migration and microvascular tube formation via paracrine signaling. Furthermore, the preserved LDH nanoplatform synergized with the ROS-depleted microenvironment to regulate bone metabolism, enhancing the osteogenic differentiation and matrix mineralization of bone marrow mesenchymal stem cells (BMSCs) while suppressing RANKL-induced osteoclastogenesis in bone marrow-derived macrophages (BMDMs). In vivo evaluations in an ovariectomized (OVX) rat critical-sized femoral defect model demonstrated that the MnO 2 @LDHs/GelMA hydrogel significantly attenuated inflammatory infiltration, re-established bone remodeling homeostasis, and accelerated vascularized bone regeneration. Conclusion This microenvironment-remodeling strategy highlights the therapeutic potential of integrating nanozymes with two-dimensional (2D) nanoplatforms, offering a promising nanobiomaterial-based approach for osteoporotic bone repair.