Multi-modal microcarriers reprogram mitochondrial metabolism and activate efferocytosis in macrophages for...

Osteoporotic bone repair remains challenging due to the ineffectiveness of traditional bone repair materials in adapting to the complex immune microenvironment of aging bone tissue. Exploiting the key role of macrophages in regulating this immune environment through the rational design of osteoimmunomodulatory biomaterials has emerged as a promising approach. However, current designs inadequately address the complexity of macrophage functions in aging environments, resulting in suboptimal regulatory effects. Hence, we explored multi-modal microcarriers for enhancing macrophage functionality. In this work, we developed a VGX-1027-loaded mesoporous silica nanosphere composite PLLA microcarrier. The dual-carrier system, featuring a micro-nano hybrid design by spatially separating the mesoporous silica nanoparticles and PLLA microspheres, enables sustained intracellular release of VGX-1027, addressing the chronic nature of osteoporotic fractures. Our studies demonstrate this VGX-1027 microcarrier (PMVGX) promotes M2 macrophage polarization by reprogramming mitochondrial metabolism. Simultaneously, it enhances efferocytosis, facilitating the clearance of dead or senescent cells and reducing inflammatory responses, thus reshaping the aging osteoimmunomodulatory. Furthermore, PMVGX induces macrophages to release osteogenic exosomes containing miR-5106 through paracrine signaling, significantly enhancing osteogenic function. In a postmenopausal osteoporosis animal model, PMVGX exhibited remarkable efficacy in repairing osteoporotic bone defects. This proof-of-concept study demonstrates that our multi-modal microcarrier effectively regulates macrophage functions via mitochondrial homeostasis, efferocytosis, and exosome content, offering great potential for osteoporotic bone repair.