Ultrasound-Mediated Targeted Delivery of ROS-Responsive Scavenging Nanomicelles for the Treatment of Ischemic Stroke.

PURPOSE: Ischemic stroke (IS) is a highly disabling and fatal cerebrovascular disease. Current vascular recanalization often triggers an explosive burst of reactive oxygen species (ROS) and a subsequent neuroinflammatory storm, leading to severe reperfusion injury. However, existing neuroprotective strategies face dual translational bottlenecks: the blood-brain barrier (BBB) restricts drug penetration, and conventional carriers cannot precisely modulate the deep ischemic microenvironment. To overcome these limitations, this study developed a dual-targeted delivery strategy combining low-intensity pulsed ultrasound with microbubbles (LIPUS-MBs) and ROS-responsive scavenging anti-inflammatory nanomicelles (TPLN).

RESULTS

The ROS-responsive scavenging TPLN nanomicelles were successfully synthesized. In vitro experiments demonstrated that TPLN efficiently scavenged intracellular ROS, protected PC12 neurons from oxygen-glucose deprivation (OGD)-induced apoptosis, and promoted the M2 repolarization of BV2 microglia. In vivo, the acoustic cavitation of LIPUS-MBs safely and reversibly permeabilized the BBB, increasing the targeted accumulation of TPLN within the ischemic lesion of MCAO rats. TPLN effectively mitigated oxidative damage and drove microglial polarization from a pro-inflammatory M1 state to a neuroreparative M2 phenotype, interrupting the oxidative stress-neuroinflammation cycle. Consequently, this synergistic therapy reduced cerebral infarct volume, alleviated brain edema, and facilitated neurological functional recovery.

CONCLUSION

The dual-targeted delivery system combining LIPUS-MBs-mediated physical BBB opening and ROS-responsive scavenging TPLN chemical targeting provides a highly translatable therapeutic platform for the precision management of ischemic stroke. However, as these findings are primarily based on an acute-phase rodent model, the long-term therapeutic effects and clinical translational applicability require further investigation.