Dual‐Responsive Dynamic Covalent Bond‐Based Assembly of Lipid‐Nanozyme Systems via Multi‐Target Synergy and Efficient Target Enrichment for Ischemic Stroke Therapy

To address the key challenges in ischemic stroke treatment-inadequate multi-target intervention, low blood-brain barrier (BBB) permeability, and lack of lesion-specific drug release-we developed an innovative pH/ROS dual-responsive lipid-nanozyme system, PBB@AHA. The system features a biomimetic phospholipid dual-tail structure that dynamically integrates the iNOS inhibitor N3, the neuroprotective agent PCA, and a vitamin E-based derivative VES-APBA via dynamic covalent bonding, followed by electrostatic self-assembly with Prussian blue nanozyme (PBB) to form a synergistic therapeutic platform. Notably, VES-APBA leverages its lipid-like properties to efficiently cross the BBB through passive diffusion and active transport, achieving effective accumulation at the lesion site. Under the characteristic acidic pH and elevated ROS levels of the ischemic microenvironment, the dual-responsive bonds cleave, triggering synchronous release of PBB (for ROS scavenging), N3 (for anti-inflammation), and PCA (for anti-apoptosis and neuroprotection), thereby collectively blocking the oxidative stress-inflammation-apoptosis multi-target pathway. In a rat model, PBB@AHA significantly reduced infarct volume by 81.7 ± 3.3% and improved neurological function scores by 73.2 ± 4.1%, offering a novel and precise nanomedicine strategy for stroke treatment.