Codelivery of fibronectin and rapamycin via bioactive phosphorus dendrimers to ameliorate Alzheimer’s disease through macrophage autophagy, oxidative stress alleviation and polarization modulation

Abstract

The primary pathogenic mechanisms underlying neurodegenerative diseases such as Alzheimer’s disease (AD) involve neuroinflammation, oxidative stress and abnormal protein aggregation, while the main challenges facing effective treatment are limited drug targeting capabilities and the blood-brain barrier (BBB) that impedes drug delivery to damaged brain regions. To address these challenges, a nanosystem based on complexes of bioactive per se phosphorus dendrimers (AK-76) with hydroxyl surface groups and protein fibronectin (FN) with both targeting and therapeutic functions that were physically loaded with rapamycin was developed. The resulting R@A/F (R for rapamycin, A for dendrimer, and F for FN) nanocomplexes (NCs) with a size of 187.3 nm demonstrate good stability, cytocompatibility and targeting performance. We show that the R@A/F NCs can cooperatively modulate microglia by lowering reactive oxygen species level, restoring mitochondrial membrane potential, enhancing autophagy, promoting microglia M2 polarization, and suppressing inflammatory cytokine secretion in vitro. With the assistance of dendrimer terminal hydroxyl groups, the R@A/F NCs can cross the BBB and improve cognitive and memory impairments in an AD mouse model by reducing brain inflammation, stimulating autophagy and facilitating Aβ protein degradation. Our study offers a versatile and highly adaptable nanoplatform for advancing the combined treatment of neuroinflammatory diseases, thus representing a significant step forward in addressing the challenges of AD therapy.