Bioinspired Immunomodulatory Scaffold Based on Mineralized Lotus Stalks Laden with MnCO Microspheres for Accelerated Bone Regeneration

Abstract Bone regeneration remains a significant clinical challenge due to the complexity of the bone healing process and the need for biomaterials that provide both structural support and immunomodulatory functions. Here, a bioinspired immunomodulatory scaffold is developed, composed of mineralized decellularized lotus stalks (MDL) integrated with manganese carbonyl (MnCO)‐loaded mesoporous polydopamine (mPDA) microspheres (MM@MDL3). This scaffold mimics the hierarchical architecture of natural bone while offering controlled CO and Mn 2+ release, promoting M2 macrophage polarization, reducing inflammation, and enhancing osteogenesis. In vitro studies demonstrate that MM@MDL3 effectively promotes mesenchymal stem cell (MSC) differentiation by activating the BMP2/SMAD/RUNX2 pathway. In vivo rat calvarial defect models confirm significant bone regeneration, with increased bone volume, enhanced vascularization, and reduced osteoclastogenesis. These results demonstrate MM@MDL3 as a promising strategy for large‐segment bone defect repair by integrating a biomimetic structure with immunomodulatory and osteogenic properties. The proposed scaffold has great potential for treating clinical large‐segment bone defects.