Poly (Lipoic Acid) Nanoparticles With High Blood-Brain Barrier Permeability and Enhanced Anti-Ferroptotic Activity for Ischemic Stroke Treatment.

Lipoic acid (LA) scavenges free radicals and was clinically tested for ischemic stroke. However, the short half-life and weak efficacy in penetrating the blood-brain barrier (BBB) limit its use in the brain. Here, we developed poly (lipoic acid) nanoparticles (pLANs) with a half-life of more than 15 h and a high efficiency to penetrate the BBB for ischemic stroke treatment. With intraperitoneal injection, imaging studies using fluorescently labelled pLANs of different sizes revealed that 30 nm pLANs entered the brain most rapidly and provided the strongest protection against ischemic injury. In vitro, 30 nm pLANs significantly prevented cell death induced by oxygen-glucose deprivation (OGD), reduced total ROS and lipid peroxides, and inhibited GPX4-dependent ferroptosis. In rat models of cerebral ischemia/reperfusion, 30 nm pLANs extended the therapeutic window by 3 h relative to LA monomer and prevented neuronal damage effectively at only half the dose. These findings demonstrate that 30 nm pLANs effectively cross the BBB, sustain drug levels in blood, and protect against neuronal death by suppressing ferroptosis, offering a promising strategy for ischemic stroke and other neurological disorders associated with oxidative stress.