Chiral nanoparticles drive enantiomer-specific osteogenic differentiation of stem cells and accelerate bone regeneration

Precise control over stem cell differentiation is of crucial importance in regenerative medicine, such as stem cell–based bone repair. Chiral nanoparticles (NPs) exhibit enantiomer-dependent interactions with stem cells, providing a promising strategy for guiding cell behaviors. Here, we investigated the role of chiral NPs in modulating osteogenic differentiation of stem cells. L-CF-NPs, D-CF-NPs, and A-CF-NPs with controllable nanoscale chirality were synthesized to investigate the effect of enantioselectivity on stem cell fate. In vitro, L-CF-NPs resulted in the highest cellular uptake through clathrin-mediated, integrin-involved endocytosis. This led to the most pronounced up-regulation of osteogenic marker expression, mineralization (via MAPK/JNK/ERK), and angiogenic marker expression. In vivo, volumetric 3D-bioprinted scaffolds incorporating L-CF-NPs resulted in the fastest bone regeneration in a rat model of critical-size bone defects. This work establishes nanoscale chirality as a design parameter for biomaterials, offering a promising approach to regenerating bone and other tissues.