Monocyte Backpack Delivery of Engineered MCF-7 Exosomes for the Treatment of Early Stage Type 1 Diabetes.

Abstract

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by autoimmune-mediated destruction of pancreatic β-cells through cytotoxic T lymphocyte infiltration, leading to absolute insulin deficiency. Supplementation of exogenous insulin can't protect remaining β-cells or address the root autoimmune cause. The emerging therapeutic strategies focus on immunomodulatory approaches, targeting the activation of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway could attenuate T cell-mediated β-cell destruction, thereby alleviating inflammation in early-stage T1DM. However, nonselective PD-1/PD-L1 blockade can cause toxicity. Herein, exosomes from PD-L1^high MCF-7 cells are utilized, modified with monocyte-targeting IgG, and have their contents removed via electroporation to eliminate tumorigenicity. Monocytes have the characteristic of targeting inflammatory sites. rExo-IgG is stably anchored to the monocytes' membrane through IgG and transported as a backpack of monocytes to the inflammatory sites (pancreas and wounds). In the pancreatic tissue, rExo-IgG through PD-1/PD-L1 pathway, inhibiting their activation and protecting β-cells. At the site of tissue injury, rExo-IgG repolarizes macrophages from pro-inflammatory M1 to anti-inflammatory M2. It also promotes fibroblast proliferation and migration, enhancing tissue regeneration. This dual-targeting exosome platform not only exhibits therapeutic efficacy against early-stage T1DM but also offers a novel strategy for the treatment of diabetic wound healing disorders.