Engineered 4-OI-loaded exosomes guide M/Ms glycolysis against ischemic stroke in aged rats

Targeting macrophages/microglia (M/Ms) dysregulated metabolism treatments have shown promise in the clinic and biomedical research. However, existing treatments are ineffective and have severe side effects. Activated M/Ms switch from oxidative phosphorylation to aerobic glycolysis, providing a poten-tial therapeutic target for inflammatory diseases. Moreover, M/Ms polarization has been shown to brain homeostasis. Bone marrow has been served as an excellent source for metabolic disorders. Here, we reported bone marrow-derived macrophages (BMDMs)-derived nanovesicles (loaded 4-octyl itacona, C-OI) that could target to M/Ms polarization and metabolism in vivo and in vitro. These nanovesicles administered to M1 M/Ms or middle cerebral artery occlusion (MCAO) rats effectively accumulated in the inflamed M/Ms, inducing a cascade of anti-inflammatory events via glycolysis reprogramming. These nanovesicles showed biological stability and compatibility, improved M/Ms metabolism, where it effectively inhibits the reactive oxygen species and neuroninflammation in injured brain tissues in MCAO rats. C-OI also suppresses MCAO-induced injury by inhibiting the activation of M1 M/Ms and secretion of proinflammatory cytokines, thus achieving satisfactory prevention and treatment in neuro-protective therapy. The engineered nanovesicles showed potential therapeutic to reprogram the brain hyperinflammation microenvironment after MCAO.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Engineered bone marrow-derived macrophage nanovesicles can target the polarization and metabolism of macrophages/microglia, potentially providing therapeutic benefits for inflammatory diseases and brain injuries.