Edaravone-loaded ROS-responsive nanosystem for targeted ischemic stroke therapy by crossing the gut-brain barrier.

Oral administration is highly desirable for sustained ischemic stroke management. However, clinical efficacy is often limited by poor intestinal absorption, restricted blood-brain barrier (BBB) penetration, and insufficient brain retention. To overcome these challenges, we engineered an equilibrative nucleoside transporter 2 (ENT2)-mediated, reactive oxygen species (ROS)-responsive, and size-transformable nanoplatform (LAG-PA/PMP NPs). The system is self-assembled from an amphiphilic lipoic acid-guanine (LAG) conjugate and phenylboronic acid (PA), encapsulating the neuroprotectant edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, PMP). Guanine serves as a targeting ligand for ENT2, which is highly expressed in intestinal epithelial cells and brain microvascular endothelial cells, thereby facilitating dual crossing of the intestinal epithelial barrier and BBB. Cross-linked disulfide bonds in alpha-lipoic acid enhance the stability of the system, while allowing cleavage under ROS-rich microenvironments to trigger controlled drug release. ROS cleaves the B-O bonds in phenylboronic acid, transforming LAG-PA/PMP NPs into larger particle structures, enhancing brain retention, and further accelerating disulfide bond cleavage to trigger PMP release. The oral bioavailability of this nanosystem is high (86.1%) with no significant toxicity. In both short- and long-term treatment models of MCAO rats, LAG-PA/PMP NPs reduced cerebral infarction volume, lowered inflammation and oxidative stress levels, and exhibited superior neuroprotective effects compared with oral free PMP. Altogether, this dual-targeting, morphology-adaptable nanoplatform provides a promising strategy for highly efficient oral therapy of ischemic stroke.