ROS-responsive nanocarriers for the delivery of atorvastatin in ischemic MCAO rats promoting neuroprotection

Ischemic stroke remains a major global public health burden, ranking among the leading causes of long-term neurological disability and mortality. Despite advances in acute care, drug delivery to injured brain tissue is hindered by the poor permeability of the blood-brain barrier (BBB), a challenge exacerbated by excess reactive oxygen species (ROS), particularly hydrogen peroxide (H₂O₂), produced during ischemia-reperfusion. This oxidative surge also offers an opportunity to design ROS-responsive, site-specific therapeutic delivery systems. Therefore, this study aims to develop PEGylated thioketal-based nanocarriers (PTC) loaded with atorvastatin, a statin with both neuroprotective and anti-inflammatory properties. The thioketal linker in PTC undergoes selective cleavage by H₂O₂, enabling the nanocarrier to function as both a smart drug delivery vehicle and an ROS scavenger. In vitro experiments using oxygen-glucose deprivation-treated BV-2 microglial cells demonstrated that PTC-statin significantly lowered intracellular ROS, inhibited lipid peroxidation, and reduced inflammatory cytokine release. In vivo, intravenous PTC-statin administration in a rat middle cerebral artery occlusion model significantly reduced infarct size, improved motor coordination (p = 0.032), and enhanced neurological outcomes (p = 0.002), with MRI confirming infarct reduction as early as day 5 (p = 0.02). Molecular and histological analyses further revealed restored BBB integrity, reduced neuronal apoptosis, and promoted neurogenesis. Overall, these findings highlight PTC-statin as a precision nanomedicine that enables site-specific, ROS-triggered drug release and mitigates oxidative damage, offering a targeted therapeutic strategy for ischemic stroke recovery.