Exosome-like nanovesicles derived from Momordica charantia ameliorate delayed t-PA thrombolysis-induced hemorrhagic transformation by inhibiting the ONOO−/HMGB1/MMP-9 pathway

Hemorrhagic transformation (HT) and restrictive therapeutic time window are significant limitations of delayed t-PA (tissue-type plasminogen activator) thrombolytic therapy in ischemic stroke patients. Plant Momordica charantia-derived exosome-like nanovesicles (MC-ELNs) can protect the blood–brain barrier (BBB) and inhibit neuronal apoptosis in stroke rats by inhibiting matrix metalloproteinase 9(MMP-9) expression. This study explored the therapeutic function and underlying mechanisms of MC-ELNs in treating HT. In delayed t-PA-treated ischemia-reperfusion rats, MC-ELNs significantly reduced mortality, HT, and cell apoptosis; MC-ELNs improved neurological function and BBB's integrity. MC-ELNs reduced ONOO− and MMP-9 expression and inhibited the release of HMGB1 from intracellular to extracellular in vivo and in vitro. ONOO− donor SIN-1 directly induced extracellular secretion of HMGB1, MC-ELNs and FeTmPyP (ONOO− decomposition catalyst, PDC) significantly reduced the expression of HMGB1 and inhibited MMP-9 activation in vitro. These findings indicate that MC-ELNs could protect BBB integrity and improve t-PA-induced HT by inhibiting the ONOO−/HMGB1/MMP-9 pathway.