Senescence-regulating agents remodel mesenchymal stem cell-schwann cell circuitry for diabetic bone regeneration.

Bone healing requires Schwann cells (SCs) paracrine factors for mesenchymal stem cell function. Diabetes mellitus (DM) patients are susceptible to developing SCs dysfunction and impairing bone healing. Rare research considered reconstructing mesenchymal stem cell-schwann cell circuitry in diabetic bone regeneration. Here we found that SCs in diabetic microenvironment appeared cellular senescence phenotype with excessive reactive oxygen species (ROS) and mitochondrial dysfunction. To target at senescent SCs, we co-entrapped small interfering RNA that targets P53 (Si-P53) and metformin (MET) in ZIF-8-based nanoparticles (MMZ@Si-P53). Mechanistically, MMZ@Si-P53 affected senescent SCs by promoting mitochondria recovery and serine biosynthesis. In addition, rejuvenation of SCs and recovery of mesenchymal stem cell-schwann cell circuitry inhibited bone marrow mesenchymal stem cells (BMSCs) senescence and improved BMSCs ossification. Subsequently MMZ@Si-P53 loaded into glucose-responsive hydrogel system (MMZ@Si-P53/HAMA-PBA-PVA) for triggering release of nanoparticles in hyperglycemia. MMZ@Si-P53/HAMA-PBA-PVA strongly promoted diabetic bone regeneration in diabetic rat model. Our findings demonstrated the effectiveness of MMZ@Si-P53/HAMA-PBA-PVA system in repairing diabetic bone defects.