ROS-responsive ecdysterone nanodelivery system ameliorates Alzheimer's disease via synergistic modulation of oxidative stress and amyloid-β deposition

Alzheimer's disease (AD), a prototypical neurodegenerative disorder, is pathologically characterized by amyloid-β (Aβ) deposition, hyperphosphorylated Tau protein accumulation, and oxidative stress cascades. Current therapeutic strategies are constrained by limited blood-brain barrier (BBB) penetration efficiency and insufficient targeting specificity. This study developed a brain-targeting intelligent nanodelivery system (CC-Ang@ECR) based on the natural pleiotropic neuroprotectant ecdysterone (ECR) to synergistically modulate AD pathological networks. The system employs carboxymethyl chitosan (CMCS) as the backbone, functionalized with hydrophobic 4-carboxyphenylboronic acid (CPBA) to construct a ROS-responsive amphiphilic polymer (CMCS-CPBA, abbreviated as CC), and further modified with Ang-2 peptide for targeted engagement of LRP receptors on BBB endothelial cells, enabling efficient brain delivery. The nanocarrier encapsulates hydrophobic ECR via hydrophobic interactions, achieves BBB transcytosis through Ang-2 peptide mediation, and releases ECR precisely in AD lesions via CPBA hydrolysis triggered by elevated ROS microenvironments. In vitro and in vivo studies demonstrate that CC-Ang@ECR effectively scavenges excessive ROS, suppresses oxidative stress, attenuates aberrant Aβ deposition, downregulates pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), inhibits neuronal apoptosis, and ultimately ameliorates cognitive and motor impairments. This system overcomes the BBB limitations and off-target risks inherent to conventional therapies, providing an innovative solution for synergistic AD therapy.