Transplantation of engineered exosomes derived from bone marrow mesenchymal stromal cells ameliorate diabetic peripheral neuropathy under electrical stimulation

Diabetic peripheral neuropathy(DPN)is a long-term complication associated with nerve dysfunction and uncontrolled hyperglycemia.In spite of new drug discoveries,development of effective therapy is much needed to cure DPN.Here,we have developed a combinatorial approach to provide biochemical and electrical cues,considered to be important for nerve regeneration.Exosomes derived from bone marrow mesenchymal stromal cells(BMSCs)were fused with polypyrrole nanoparticles(PpyNps)containing liposomes to deliver both the cues in a single delivery vehicle.We developed DPN rat model and injected intramuscularly the fused exosomal system to understand its long-term therapeutic effect.We found that the fused system along with electrical stimulation normalized the nerve conduction velocity(57.60±0.45 m/s)and compound muscle action potential(16.96±0.73 mV)similar to healthy control(58.53±1.10 m/s;18.19±1.45 mV).Gastrocnemius muscle morphology,muscle mass,and integrity were recovered after treatment.Interestingly,we also observed paracrine effect of delivered exosomes in controlling hyperglycemia and loss in body weight and also showed attenuation of damage to the tissues such as the pancreas,kidney,and liver.This work provides a promising effective treatment and also contribute cutting edge therapeutic approach for the treatment of DPN.