Innovations in Nanotechnology-based Drug Delivery for Ischemic Stroke

Abstract

The blood-brain barrier (BBB) blocks over 98% of neuroactive drugs from reaching the brain, constituting a major obstacle to effective treatment for ischemic stroke. Nanotechnology offers innovative solutions for overcoming this barrier; however, the field currently lacks a unified framework to guide the rational design of nanocarriers. This study aims to systematically evaluate nanotechnology-based drug delivery systems for ischemic stroke according to their underlying BBB transport mechanisms-namely, adsorption-mediated transport (AMT), receptor-mediated transport (RMT), and cell-mediated transport (CMT)-and to validate the hypothesis that CMT strategies are superior for targeted delivery to the ischemic hemisphere. In a murine MCAO model, targeted nanoparticles were employed alongside a non-targeted control for original validation (n = 3/group; 60-minute occlusion; 5 mg/kg intravenous dose). Outcomes included NIR-II fluorescence imaging (1-24 hours), T2-weighted MRI (72 hours), histology, immunofluorescence, TUNEL apoptosis assays, and RNA-seq transcriptomics. Compared to the AMT/RMT methods, CMT-based strategies-exemplified by neutrophil "hitchhiking" (and neutrophil elastase inhibition -demonstrated superior accumulation within the ischemic hemisphere. Targeted Nano treatment achieved: (i) significantly enhanced cerebral fluorescence at 8 hours compared to non-targeted Nano treatment (ii) a reduction in infarct volume from (iii) reduced neutrophil infiltration and decreased apoptosis (iv) preservation of blood-brain barrier integrity and reduced Evans blue extravasation; (v) absence of acute organ toxicity; and (vi) normalization of transcriptomic pathways associated with inflammation (TNF, NF-κB, IL-17) and oxidative stress. Endogenous cell-mediated transport(CMT) represents a superior strategy for traversing the blood-brain barrier in ischemic stroke, enabling the attainment of therapeutic drug concentrations at the lesion site while simultaneously mitigating systemic toxicity. Neutrophil-targeted nanotherapy-whether achieved through drug-loaded nanoparticle "hitchhiking" or the inhibition of neutrophil elastase-offers a paradigm-shifting approach to the treatment of acute ischemic stroke.