Abstract: Peripheral neuropathy is one of the major common complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function caused by diabetic peripheral neuropathy (DPN). Communications between Schwann cells and sciatic nerves of dorsal root ganglia (DRG) neurons maintain homeostasis of peripheral nerve function. Exosomes, endosome-derived nano vesicles carry RNAs and proteins as their molecular cargo. Exosomes mediate intercellular communication by transferring their cargo between source and recipient cells. Our preliminary data showed that treatment of type II diabetes db/db mice with Schwann cell derived exosomes (SC-Exos) remarkably ameliorated neurological dysfunction of DPN, which was associated with significant augmentation of intraepidermal nerve fibers and myelinated axons of the sciatic nerve. We also found that intravenously administered SC-Exos were internalized by Schwann cells and nerve fibers of the sciatic nerve, suggesting that SC-Exos act on Schwann cells and sciatic nerves. Our preliminary data also showed that the SC-Exo treatment did not significantly change blood glucose and glycosylated hemoglobin (HbA1c) levels and liver function; however, importantly, SC-Exos reversed a network of miRNAs and proteins in the sciatic nerve tissues that mediate development of DPN. Based on these preliminary data, using a clinically relevant mouse model of high fat diet/streptozotocin-induced Type 2 diabetes, we propose to test the hypothesis that SC-Exos interact with Schwann cells and sciatic nerves to modulate this network of miRNAs and proteins and thereby ameliorate DPN. We will first examine whether the miRNA cargo of SC-Exo contribute to the therapeutic effect of SC-Exos on DPN. We will then examine whether endogenous miRNAs in Schwann cells and in the sciatic nerve of dorsal root ganglion (DRG) enhance the therapeutic effect of SC-Exo. Subsequently, we will examine whether engineered SC-Exos carrying elevated selected miRNAs to suppress genes that induce axonal injury and demyelination further reduce neurological dysfunction of DPN. Relevance Statement: Diabetic peripheral neuropathy is a major disability affecting millions of Americans. In this proposal, employing clinically relevant animal models of diabetic peripheral neuropathy, we seek to develop a novel therapeutic approach to treat diabetic peripheral neuropathy using exosomes derived from healthy Schwann cells. In this proposal, we will also elucidate the molecular mechanisms by which exosomes are therapeutically effective. This research will potentially provide the essential pre-clinical data for translation of this novel therapeutic approach to a phase 1 clinical trial.