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Article Abstract
For sustained ischemic stroke intervention, oral delivery remains optimal. However, conventional nanocarriers like liposomes fail to overcome both the intestinal epithelial (IEB) and blood-brain barriers (BBB). We engineered dual-functional, butylphthalide (NBP)-loaded liposomes (C-NBP Lip) via amphiphilic cytidine-lipoic acid conjugate (LA-C) functionalization, establishing the first unified nanoplatform for nucleoside transporter-mediated targeting and reactive oxygen species (ROS)-responsive membrane modulation. Our strategy exploits cytidine's dual affinity for apical concentrative (CNT1) and basolateral equilibrative (ENT1) nucleoside transporters on gut epithelia, enabling efficient intestinal translocation and subsequent ENT1-mediated BBB transcytosis via a single ligand. Crucially, hydrophobic interactions between LA-C's dithiolane ring and phospholipids dynamically tuned membrane rigidity of C-NBP Lip. enabling ROS-triggered drug release at ischemic lesions. In rats, C-NBP Lip exhibited 44.61 % oral bioavailability, 137 % higher than free NBP (18.80 %), and demonstrated robust neuroprotection without toxicity in both short- and long-term rat ischemic stroke model. This work pioneers "barrier-adaptive liposomes" that integrate endogenous transporter exploitation with stimulus-responsive membrane engineering for transformative oral brain delivery.
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| http://dx.doi.org/10.1016/j.jconrel.2025.113955 | DOI Listing |
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