Osteogenic Differentiation Triggered by Intracellular Magnetoelectric Stimulation of Core–Shell Nanotransducers under Remotely Applied Magnetic Fields

Magnetoelectric nanoparticles (MENPs), combining a magnetostrictive core with a piezoelectric shell, offer a promising route for remote-controlled biomedical applications by converting external magnetic fields into electric cues. However, the clinical translation of these materials remains limited due to the toxicity of high-performance piezoelectric materials, which typically contain lead. Previously, we developed lead-free MENPs comprising manganese ferrite oxide (MFO) core nanoparticles (NPs) coated with a Ba_0.85Ca_0.15Zr₀.₁Ti_0.9O₃ (BCZT) piezoelectric shell (MFO@BCZT). While these nanotransducers exhibit robust magnetic responsiveness and piezoelectric performance comparable to lead-based ceramics, their role in producing in situ electrical cues to accelerate bone repair remains unexplored. Given the established role of electrical stimulation in bone remodeling, this study explores the potential of MFO@BCZT MENPs to promote the osteogenic differentiation of human adipose-derived stem cells (hASCs) after internalization, assembly into magnetized 3D spheroids, and subsequent embedding in gelatin methacryloyl hydrogels, to better recapitulate physiologically relevant microenvironments. Differentiation was assessed under static and cyclic magnetic field (CMF) conditions and compared to spheroids containing bare MFO NPs and spheroids without NPs. Results revealed that MFO and MFO@BCZT NPs were cytocompatible; however, MFO@BCZT MENPs significantly enhanced osteogenic marker expression and mineral deposition compared to both controls, with CMF further amplifying these effects. Under CMF stimulation, MFO@BCZT MENPs produced a mineralized matrix with a calcium-to-phosphorus molar ratio of 1.67, aligning precisely with native bone apatite. Overall, by restoring the bioelectric properties of bone at the target region, this study positions MFO@BCZT MENPs as a compelling platform for future smart bone therapies.