Multifunctional scaffold inspired by hepatocyte exosomes promotes bone regeneration by regulating osteogenic differentiation via PI3K/AKT pathway.

Exosome-mediated tissue-tissue communication represents a fundamental mechanism that maintains physiological homeostasis. This study proposes a novel therapeutic approach based on liver-bone cross-talk, wherein hepatocyte-derived exosomes (h-EXOs) markedly accelerated the repair of critical cranial defects. Specifically, h-EXOs were anchored onto a digital light processing (DLP)-printed scaffold (PH/PDA) composed of polycaprolactone macromolecule polymer (PCLMA) and nano-hydroxyapatite (nHap) via a polydopamine (PDA) coating to promote cranial bone regeneration. These PH/PDA scaffolds substantially enhanced bone mesenchymal stem cells (BMSCs) adhesion and proliferation, while the incorporated h-EXOs significantly promoted angiogenesis and osteogenic differentiation. Moreover, RNA sequencing revealed that h-EXOs were enriched in cargoes governing diverse cellular processes and activated the PI3K/AKT pathway to promote BMSCs osteogenesis. Following implantation, PH/PDA/h-EXOs scaffolds induced substantial defect closure and fostered a regenerative microenvironment similar to native calvarial tissue, characterized by an expansion of anti-inflammatory M2 macrophages and osteoblasts alongside pronounced vascularization. Overall, this study leverages inter-organ crosstalk in conjunction with personalized scaffold fabrication to propose a novel tissue-engineering strategy for enhancing tissue repair.