Nano‐Brake Halts Mitochondrial Dysfunction Cascade to Alleviate Neuropathology and Rescue Alzheimer's Cognitive Deficits

Abstract

Mitochondrial dysfunction has been recognized as the key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). The dysregulation of mitochondrial calcium ion (Ca2+) homeostasis and the mitochondrial permeability transition pore (mPTP), is a critical upstream signaling pathway that contributes to the mitochondrial dysfunction cascade in AD pathogenesis. Herein, a “two‐hit braking” therapeutic strategy to synergistically halt mitochondrial Ca2+ overload and mPTP opening to put the mitochondrial dysfunction cascade on a brake is proposed. To achieve this goal, magnesium ion (Mg2+), a natural Ca2+ antagonist, and siRNA to the central mPTP regulator cyclophilin D (CypD), are co‐encapsulated into the designed nano‐brake; A matrix metalloproteinase 9 (MMP9) activatable cell‐penetrating peptide (MAP) is anchored on the surface of nano‐brake to overcome the blood‐brain barrier (BBB) and realize targeted delivery to the mitochondrial dysfunction cells of the brain. Nano‐brake treatment efficiently halts the mitochondrial dysfunction cascade in the cerebrovascular endothelial cells, neurons, and microglia and powerfully alleviates AD neuropathology and rescues cognitive deficits. These findings collectively demonstrate the potential of advanced design of nanotherapeutics to halt the key upstream signaling pathways of mitochondrial dysfunction to provide a powerful strategy for AD modifying therapy.

In Situ Self-Assembled Phytopolyphenol-Coordinated Intelligent Nanotherapeutics for Multipronged Management of Ferroptosis-Driven Alzheimer’s Disease

“…Next, the novelty recognition memory based on innate curiosity in mice was assessed by the novel object recognition (NOR) test and the Y-maze test, respectively . For the NOR test, one of the familiar objects in the training phase was replaced with a novel object in the testing phase to examine the mice’s exploration preference for the novel object (Figure f).…”

“…Next, the novelty recognition memory based on innate curiosity in mice was assessed by the novel object recognition (NOR) test and the Y-maze test, respectively. 46 For the NOR test, one of the familiar objects in the training phase was replaced with a novel object in the testing phase to examine the mice's exploration preference for the novel object (Figure 6f). It was found that the preference index and the discrimination index for the novel object were much lower in the AD mice than in the WT mice, which were greatly increased by TQCN treatment to almost the same level as that of the WT mice (Figure 6g,h).…”

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

“…It decreased CypD expression by 44.9%, inhibited Drp1 expression, and enhanced OPA1 expression to halt the mitochondrial dysfunction cascade. [226] Regulation of inflammation-related pathways (including upward and downward regulation) [227,228] can also enhance mitochondrial protection by cutting off the vicious circle between inflammation and other pathological phenomena such as oxidative stress. [229,230] Ac2-26, an Annexin 1(ANXA1) derived peptide, can prevent neutrophils from infiltrating and adhering by acting on the lipotoxin A4 receptor (ALXR/FPRL1) on the cell surface to repress inflammation.…”

Matrix Metalloproteinase-Responsive Drug Delivery Systems

“…The MAP-decorated lipid nanocarrier targets the impaired cerebral microvasculature and can efficiently achieve intracerebral delivery in mouse models of AD, attenuating mitochondria impairment and neurovascular system damage in their brains. The nanobrake is safe and rescues cognitive deficits in AD mice …”

“…The nanobrake is safe and rescues cognitive deficits in AD mice. 86 MMP-responsive drug delivery systems are sparingly employed to treat the nervous system diseases. Yet, the severity and high incidence of nervous system diseases constitute a substantial hazard to human health.…”