Enhanced nasal-to-brain drug delivery by multivalent bioadhesive nanoparticle clusters for cerebral ischemic reperfusion injury protection.

Following cerebral ischemia, reperfusion injury can worsen ischemia-induced functional, metabolic disturbances, and pathological damage upon blood flow restoration, potentially leading to irreversible harm. Yet, there's a dearth of advanced, localized drug delivery systems ensuring active pharmaceutical ingredient (API) efficacy in cerebral protection during ischemia-reperfusion. This study introduces a multivalent bioadhesive nanoparticle-cluster, merging bioadhesive nanoparticles (BNPs) with dendritic polyamidoamine (PAMAM), enhancing nose-to-brain delivery and brain protection efficacy against cerebral ischemia-reperfusion injuries (CIRI). The BNPs-PAMAM cluster exhibits superior adhesion within the rat nasal cavity, prolonged retention, enabling sustained drug release, cerebral transportation, and accumulation, resulting in enhanced intracerebral pharmacokinetic profile. Intranasal administration circumvents systemic delivery challenges, ensuring CIRI protection drugs reach ischemic areas pre-reperfusion, overcoming thrombus-related delays. Administering BNPs-PAMAM loaded with dexmedetomidine (DEX) pre-reperfusion effectively prevents neuron apoptosis by α2-adrenoceptor activation, modulating the ischemic microenvironment, exerting triple neuroprotective effects against cerebral reperfusion injury. Importantly, only therapeutic DEX releases and accumulates in the nasal cavity, averting brain nanomaterial toxicity, promising for repeat administrations. This study presents a translational platform for nasal-to-brain drug delivery in CNS disease treatment. STATEMENT OF SIGNIFICANCE: Innovative Drug Delivery System: This study introduces a multivalent bioadhesive nanoparticle-cluster (BNPs-PAMAM) to enhance nasal-to-brain drug delivery for cerebral ischemia-reperfusion injury (CIRI) treatment. Enhanced Retention and Efficacy: The BNPs-PAMAM system significantly improves drug retention in the nasal cavity and ensures sustained release, thereby enhancing the therapeutic efficacy of the neuroprotective agent dexmedetomidine (DEX). Blood-Brain Barrier Circumvention: By leveraging intranasal administration, the system bypasses the blood-brain barrier, delivering DEX directly to ischemic brain regions before reperfusion and minimizing systemic side effects. Triple Neuroprotective Effects for CIRI protection: DEX delivered via BNPs-PAMAM effectively reduces oxidative stress and inflammation while enhancing mitochondrial autophagy, providing comprehensive protection against neuronal damage.