PTGFRN- and IL-4-overexpressing exosome-functionalized Janus fibrous scaffolds for enhanced heterogeneous tissue regeneration.

Bone defects caused by trauma, infection, or tumor removal are often combined with soft tissue injury. This creates a major clinical problem because there are no effective methods to repair both hard and soft tissues at the same time. This study presents a strategy that combines physical and biological signals based on materiobiology and immune-guided regeneration. A Janus electrospun nanofibrous scaffold loaded with immunomodulatory exosomes (ExoPTGFRN/IL-4) was designed and fabricated. The scaffold has different surface structures and mechanical properties on each side, and it can regulate immune responses needed for both bone and muscle repair. Exosomes derived from macrophages and modified with PTGFRN and IL-4 have two main roles: targeting and reprogramming of macrophages. Evaluation of the foreign body response showed that the scaffold did not cause long-term inflammation or systemic toxicity. It also regulated fibrosis, angiogenesis, and macrophage polarization. In vitro experiments and in vivo models, including muscle injury, calvarial bone defect, and mandibular defect models, showed that ExoPTGFRN/IL-4 promoted myogenic and osteogenic differentiation while suppressing osteoclastogenesis. This led to effective soft tissue repair and bone regeneration. The ExoPTGFRN/IL-4-functionalized scaffold (PHA-ExoPTGFRN/IL-4) provides a new approach for repairing heterogeneous tissues and shows strong potential application in orthopedics and maxillofacial surgery.