A Reactive Oxygen Species‐Responsive Targeted Nanoscavenger to Promote Mitophagy for the Treatment of Alzheimer's Disease

Abstract

Mitophagy modulators are proposed as potential therapeutic intervention that enhance neuronal health and brain homeostasis in Alzheimer's disease (AD). Nevertheless, the lack of specific mitophagy inducers, low efficacies, and the severe side effects of nonselective autophagy during AD treatment have hindered their application. In this study, the P@NB nanoscavenger is designed with a reactive‐oxygen‐species‐responsive (ROS‐responsive) poly(l‐lactide‐co‐glycolide) core and a surface modified with the Beclin1 and angiopoietin‐2 peptides. Notably, nicotinamide adenine dinucleotide (NAD+) and Beclin1, which act as mitophagy promoters, are quickly released from P@NB in the presence of high ROS levels in lesions to restore mitochondrial homeostasis and induce microglia polarization toward the M2‐type, thereby enabling it to phagocytose amyloid‐peptide (Aβ). These studies demonstrate that P@NB accelerates Aβ degradation and alleviates excessive inflammatory responses by restoring autophagic flux, which ameliorates cognitive impairment in AD mice. This multitarget strategy induces autophagy/mitophagy through synergy, thereby normalizing mitochondrial dysfunction. Therefore, the developed method provides a promising AD‐therapy strategy.

Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease

“…In contrast, the M2 microglia in the AD brain is beneficial in tissue repair and neuroprotection by phagocytosing Aβ and also in decreasing brain inflammation and Aβ toxicity. 8 In response to Aβ aggregation, microglia takes on a phagocytic phenotype of disease-associated microglia (DAM)…”

“…Hyperactive M1 microglia not only could be releasing pro-inflammatory cytokines to further damage normal neurons but also weaken their phagocytosis and clearance function. In contrast, the M2 microglia in the AD brain is beneficial in tissue repair and neuroprotection by phagocytosing Aβ and also in decreasing brain inflammation and Aβ toxicity . In response to Aβ aggregation, microglia takes on a phagocytic phenotype of disease-associated microglia (DAM) with increased expression of sensor receptors and the consequential stimulation of phagocytosis .…”