Engineered Extracellular Vesicles with SHP2 High Expression Promote Mitophagy for Alzheimer's Disease Treatment

Abstract

Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment of existing mitophagy inducers limit their further applications. In this study, a platform for AD therapy is developed using nanosized mesenchymal‐stem‐cells‐derived extracellular vesicles with tyrosine phosphatase‐2 (SHP2) high‐expression (MSC‐EVs‐SHP2). The high blood–brain barrier penetration ability of MSC‐EVs‐SHP2 is demonstrated in AD‐mice, facilitating SHP2 delivery to the brain. In addition, MSC‐EVs‐SHP2 significantly induces mitophagy of neuronal cells, which alleviates mitochondrial damage‐mediated apoptosis and NLRP3 inflammasome activation. Mitophagy further diminishes neuronal cells apoptosis and neuroinflammation, culminating with rescued synaptic loss and cognitive decline in an AD mouse model. The EV‐engineering technology provides a potential platform for effective AD therapy by inducing mitophagy.

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

“…Thus, INH administration of MSC-EVs-carrying miRNAs might provide a good reference. More importantly, we found that miR-146a-5p-EVs were generally more potent than Hypo-EVs in suppressing airway inflammation and remodeling in asthmatic mice, which further supported the notion that engineering MSC-EVs is an effective way to improve the therapeutic effect of MSC-EVs ( 45 , 46 ).…”

Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease

“…Proteins as important regulator molecules, play a critical role in various disease therapies. A growing number of studies show that genetically engineered MSC-EVs containing therapeutic proteins were used in disease treatments [160][161][162]. For example, in the context of AD, Xu F et al infected MSCs with lentivirus encoding the Src homology 2 domaincontaining protein tyrosine phosphatase-2 (SHP2) gene to obtain MSC-EVs with high level of SHP2 [162].…”

“…A growing number of studies show that genetically engineered MSC-EVs containing therapeutic proteins were used in disease treatments [160][161][162]. For example, in the context of AD, Xu F et al infected MSCs with lentivirus encoding the Src homology 2 domaincontaining protein tyrosine phosphatase-2 (SHP2) gene to obtain MSC-EVs with high level of SHP2 [162]. As a result, mitophagy is significantly induced by MSC-EVs-SHP2, which ameliorates mitochondrial damage-mediated apoptosis and NLRP3 activation in neuronal cells.…”

Sniping Cancer Stem Cells with Nanomaterials

“…393 Due to their biological origin, they offer several advantages over traditional synthetic nanoparticles, including lower immunogenicity, enhanced stability, improved safety, and better cellular uptake, which have shown promising results in preclinical studies for cancer therapy. 394,395 Among cell-derived nanomaterials, cell membrane-encapsulated nanoparticles possess potential immune-evasive properties and prolonged circulation times in vivo. 396 Given this, He et al utilized red blood cell coated nanoparticles to codeliver antiapoptotic protein inhibitor ABT-263 (ABT) and A-1210477 (A12) for GBM.…”

“…Bionic nanomaterials like membrane-coated nanoparticles and extracellular vesicles show great potential in biomedical use due to their easy production, excellent biocompatibility, and ability to target tumors and evade the immune system . Due to their biological origin, they offer several advantages over traditional synthetic nanoparticles, including lower immunogenicity, enhanced stability, improved safety, and better cellular uptake, which have shown promising results in preclinical studies for cancer therapy. , …”