Supramolecular helicity dependent osteogenesis and angiogenesis crosstalk of periodontal ligament stem cell

The two pillars supporting effective tissue regeneration are multipotent stem cells and matrix materials that direct differentiation. The chirality of the extracellular matrix is a key structural characteristic that affects stem cell fate. However, little is known about the effects of either molecular chirality or supramolecular helicity on the differentiation of periodontal ligament stem cells (PDLSCs), a safe and easily accessible stem cell source. Here, we constructed fibrils through the co-assembly of chiral amino acid derivative enantiomers (<i>l</i>/<i>d</i>-GC18) and a bridging pyrazine molecule. The helicity of the fibrils depends on both the molecular chirality of the amino acid and the stoichiometric ratio of the two components. Our results showed that molecular chirality and supramolecular helicity can act synergistically, with the left-handed fibrils assembled from <i>l</i>-GC18 and pyrazine promoting osteogenic differentiation of PDLSCs <i>in vivo</i>. Moreover, the chiral fibrils effectively promoted bone regeneration in both the calvarial and alveolar bone defect models. Interestingly, it was observed that left-handed fibrils induced integrin-dependent osteogenic differentiation, which in turn stimulated Piezo1-mediated, Vascular Endothelial Growth Factor (VEGF)-driven angiogenesis. These findings thus provide a blueprint for harnessing PDLSCs in next-generation regenerative therapeutics.