Biomimetic Hierarchical Molecular Assembly of Silk‐Hydroxyapatite Composites for Near‐Native Bone Regeneration

Abstract Large‐scale bone defects pose significant clinical challenges due to limited regenerative capacity and the limitations of current therapies. Biomimetic bone graft materials, inspired by the native structure and composition of bone, offer a promising alternative. However, replicating the complex hierarchical molecular assembly of organic and inorganic components—particularly the highly oriented mineralized collagen micro/nanofibrillar structure—remains elusive. Here, a silk‐hydroxyapatite composite, BIO‐MAC (Biomimetic Integrated Organic–Mineral Assembly Composite), engineered through biomimetic assembly to emulate the chemical composition and hierarchical organization of native bone, is reported. By leveraging the interfacial adsorption between silk fibroin and hydroxyapatite, combined with β‐sheet molecular network rearrangement, we developed a mechanical training strategy is developed to align components into a highly oriented structure. BIO‐MAC exhibits near‐native mechanical properties, providing stability during bone healing and preventing stress shielding. BIO‐MAC also supports the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells, effectively accelerating near‐native bone regeneration in a rat cranial defect model. These findings underscore BIO‐MAC's potential as an effective bone graft material and establish a platform for designing biomimetic scaffolds to support regeneration in other tissues, including skin, muscle, and vascular grafts.