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.