Aβ42 and ROS dual-targeted multifunctional nanocomposite for combination therapy of Alzheimer's disease
Liding Zhang1, Kai Cao2, Jun Xie2
1State Key Laboratory of Digital Medical Engineering, Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou, 570228, China.
Abstract:
Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aβ aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer's disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aβ42, we developed an Aβ42 and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aβ-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aβ42 misfolding, accelerating Aβ42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aβ clearance exhibited by this Aβ42 and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.
Insights
This study developed a novel nanocomposite, RVG29-bMSNs@Ce-1F12, that simultaneously targets amyloid-beta (Aβ) aggregation and reactive oxygen species (ROS) to treat Alzheimer's disease (AD). This dual-action approach shows promise in alleviating AD pathology and improving cognitive function.
Area of Science:
- Neuroscience
- Nanotechnology
- Biomedical Engineering
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) aggregation and oxidative stress from reactive oxygen species (ROS).
- Current treatments often target single pathways, highlighting the need for multi-target strategies.
- Inhibiting Aβ aggregation and scavenging ROS simultaneously may offer a synergistic therapeutic effect for AD.
Purpose of the Study:
- To develop and evaluate a novel dual-targeting nanocomposite for Alzheimer's disease.
- To investigate the efficacy of simultaneous Aβ aggregation inhibition and ROS scavenging.
- To assess the brain-targeting capability and therapeutic potential of the developed nanodrug.
Main Methods:
- Development of a dual-targeting nanocomposite (RVG29-bMSNs@Ce-1F12) using biodegradable mesoporous silica nanoparticles loaded with cerium oxide nanocrystals and an anti-Aβ antibody (1F12).
- Modification of the nanocomposite with rabies virus glycoprotein 29 (RVG29) for enhanced brain targeting.
- Evaluation of the nanocomposite's efficacy in inhibiting Aβ42 misfolding, clearing Aβ42, scavenging ROS, reducing tau pathology, alleviating glial activation, and improving cognitive function in APP/PS1 mice.
Main Results:
- The RVG29-bMSNs@Ce-1F12 nanocomposite efficiently targeted Aβ-rich brain regions.
- The dual-targeting strategy significantly inhibited Aβ42 aggregation and enhanced Aβ42 clearance.
- The nanocomposite effectively scavenged ROS, reduced hyperphosphorylated tau burden, decreased glial activation, and improved cognitive function in AD mouse models.
Conclusions:
- RVG29-bMSNs@Ce-1F12 is a promising nanodrug for multi-target treatment of Alzheimer's disease.
- Simultaneous targeting of Aβ aggregation and ROS offers a synergistic therapeutic benefit.
- This approach demonstrates potential for alleviating AD pathology and restoring cognitive function.
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