Enhanced subacute ischemic stroke treatment via multistage drug delivery system design for combination therapy

The management of acute ischemic stroke remains challenging due to its abrupt onset and the narrow treatment window, resulting in high rates of disability and mortality. Combination therapy for neuroprotection and neurorepair strategies provided new hopes for subacute stroke treatment. Here we designed a multistage nanodelivery system that matches the unique microenvironment of the subacute phase of stroke, which utilizes calixarene as a building block to effectively load the neuroprotective drug simvastatin. The calixarene is designed with glycosidic linkages targeting the glucose transporter 1 (GLUT1) on the blood-brain barrier (BBB) and azo bonds that are responsive to hypoxic conditions. Additionally, the decomposed calixarene molecules themselves possess intrinsic bio-activation to modulate inflammatory responses, achieving a multistage therapeutic approach that transitions from targeting to release and finally to treatment. This approach combines anti-inflammation and neuroprotection, providing a multi-level treatment strategy. This system was validated in a rat model of permanent middle cerebral artery occlusion (pMCAO), demonstrating that intravenous administration of the nanodelivery system repairs brain damage and improves motor function 24 h post-pMCAO induction. This work offers a precise and integrative strategy for stroke patients missing the acute therapy window to improve functional recovery and enhance the effect of comprehensive treatment.