A Universal Strategy for BBB Transport Mediated by an Inflammatory Receptor Antagonist for Neuroprotection in Ischemic Stroke

Abstract

Abstract Delivering therapeutics across the blood–brain barrier (BBB) remains a major challenge in ischemic stroke therapy. Ischemic stroke induces upregulation of various inflammatory membrane receptors on brain endothelial cells, offering potential entry points for receptor‐mediated transcytosis. This study proposes a universal targeting strategy by employing inflammatory pathway antagonists as targeting ligands, which broadens the spectrum of available ligands beyond traditional receptor‐binding molecules. Notably, many antagonists not only confer receptor‐targeting ability but also actively participate in downstream anti‐inflammatory, antioxidant, or cellular repair signaling pathways. A multifunctional polyphenol‐based nanoparticle system is developed by co‐assembling oligomerized cyanidin‐3‐glucoside (C3G) with a series of receptor‐specific antagonists as targeting ligands, including those for thromboxane A2 receptor (TxA2R), Toll‐like receptors 4 and 7 (TLR4 and TLR7), and purinergic receptors (e.g., P2X4). The nanoparticles demonstrate a bifurcated intracellular fate: Golgi‐mediated transcytosis into brain parenchyma or endothelial repair via upregulation of tight junction proteins. Nanoparticles loaded with Seratrodast (CCS) are selected as a representative formulation for in‐depth evaluation. Upon entering the ischemic microenvironment, CCS nanoparticles are degraded by reactive oxygen species, releasing catechol‐containing metabolites for potent inhibition of lipoxygenase (LOX) activity, thereby blocking ferroptosis and promoting neuroprotection. These findings highlight the dual functionality of antagonists as both targeting ligands and therapeutic modulators, offering a highly translatable design paradigm for intelligent stroke therapeutics.