A carrier-free nanodrug based on the self-assembly of hydroxysafflor yellow A and ethyl ferulate for cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury (CIRI) primarily manifests through uncontrolled inflammatory reactions and oxidative stress accumulation. Hydroxysafflor yellow A (HYSA), an anti-inflammatory agent commonly used for CIRI treatment, exhibits low bioavailability because of its high water solubility, which necessitates the administration of large doses, leading to adverse side effects. In biomedical engineering, although conventional HYSA-loaded nanocarriers can address the aforementioned issues, they still exhibit several limitations, including carrier-related toxicity, low drug-loading capacity, and various tendencies such as drug crystallization and leakage during storage. To overcome these limitations, we developed carrier-free nanoparticles by covalently linking ethyl ferulate (EF) and HYSA through a reactive oxygen species (ROS)-cleavable oxalyl chloride bridge (HOE). This ROS-responsive design facilitates targeted drug release in ischemic brain regions, thereby synergistically combining the antioxidant properties of EF with the anti-inflammatory effects of HYSA. In vitro studies demonstrated that HOE significantly enhanced ROS-scavenging ability. In CIRI models, HOE markedly reduced cerebral infarct volume and improved neurological recovery compared with HYSA treatment alone, without any observable toxicity. Additionally, HOE codelivered curcumin, further enhancing therapeutic efficacy. By integrating dual therapeutic mechanisms into a self-assembling, excipient-free nanoplatform, HOE effectively overcomes dosage limitations, thereby presenting a synergistic and biocompatible strategy for CIRI treatment.