Cerium-doped prussian blue nanozymes for bone regeneration and osteoprotection by Lhx2 in sutural distraction osteogenesis through multi-omics analysis

Sutural distraction osteogenesis (SDO) involves the induction of new bone formation in the suture region through external distraction, widely employed for treating craniomaxillofacial deformities such as craniosynostosis and maxillary transverse hypoplasia. Nonetheless, there remains a deficiency in effective and minimally invasive therapeutic approaches to shorten the treatment duration and minimize the risk of relapse. Prussian blue (PB) nanozymes exhibit extensive biological applications due to their superior biocompatibility and enzyme-like activity. Incorporating cerium (Ce), which possesses REDOX and osteopromoting properties, into Prussian blue nanozymes not only preserves its excellent biosafety but also enhances stem cell recruitment and bidirectional regulation of osteogenesis promotion and osteoclast inhibition. Moreover, the bidirectional regulatory effects of cerium-doped prussian blue (CePB) nanozymes are significantly amplified under mechanical tension conditions. ANANSE (Analysis Algorithm for Networks Specified by Enhancers) analysis integrating RNA-seq, ATAC-seq, and CUT&Tag data identified Lhx2 as a critical transcription factor involved in regulating osteogenic differentiation of suture‑derived stem cells (SuSCs) mediated by CePB nanozymes, which was further validated in vitro. In summary, CePB nanozymes offer a novel adjuvant therapy for craniomaxillofacial suture distraction osteogenesis. This study provides the first in-depth, comprehensive, and reliable investigation into how nanozymes regulate stem cell fate through the integration of transcriptome analysis and epigenetic sequencing.