Bimetallic MOF‐Incorporated Hydrogel Scaffolds for Astaxanthin Delivery: Remodeling Bone Microenvironment and Accelerating Bone Repair

ABSTRACT Impaired bone regeneration in large defects is often caused by a hostile microenvironment featuring persistent inflammation, insufficient vascularization, and high oxidative stress, which collectively induce senescence and osteogenic impairment of bone marrow mesenchymal stem cells (BMSCs). Naturally derived astaxanthin is observed to reduce the expression of senescence‐associated markers and restore the proliferative and osteogenic potential of senescent BMSCs under inflammatory conditions. This study develops a composite hydrogel scaffold incorporating astaxanthin‐loaded bimetallic MOF (AST@ZnCo‐MOF) nanoparticles for accelerating bone repair. The hydrogel scaffold significantly suppresses ROS and pro‐inflammatory cytokine levels in RAW264.7 cells, promoting their polarization toward the regenerative M2 phenotype. Sustained release of Zn 2+ /Co 2+ enhances the migration and angiogenic activity of HUVECs. Furthermore, astaxanthin synergizes with metal ions to markedly enhance the proliferation and osteogenic differentiation of BMSCs, while suppressing adipogenic differentiation, thereby critically accelerating the healing of critical‐sized cranial defects. Mechanistic investigations reveal that astaxanthin localizes to the endoplasmic reticulum, binds to HSP90, and activates the IRE1α‐XBP1 axis of the unfolded protein response, leading to the upregulation of the key osteogenic transcription factor Osterix in BMSCs. This work provides a multifunctional platform and mechanistic insight for promoting large bone defect repair through coordinated immunomodulation, vascularization, and stem cell regulation.