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

Abstract

With the increase of population aging, the number of Alzheimer's disease (AD) patients is also increasing. According to current estimates, approximately 11% of people over 65 suffer from AD, and that percentage rises to 42% among people over 85. However, no effective treatment capable of decelerating or stopping AD progression is available. Furthermore, AD-targeted drugs composed of synthetic molecules pose concerns regarding biodegradation, clearance, immune response, and neurotoxicity. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are essential intercellular communication mediators holding great promise as AD therapeutics owing to their biocompatibility, versatility, effortless storage, superior safety, and the ability to transport messenger and noncoding RNAs, proteins, lipids, DNAs, and other bioactive compounds derived from cells. The functionalisation and engineering strategies of MSC-EVs are highlighted (e.g. preconditioning, drug loading, surface modification, and artificial EV fabrication), which could improve AD treatment by multiple therapeutic effects, including clearing abnormal protein accumulation and achieving neuroprotection and immunomodulatory effects. Herein, this review summarises state-of-the-art strategies to engineer MSC-EVs, discusses progress in their use as AD therapeutics, presents the perspectives and challenges associated with the related clinical applications, and concludes that engineered MSC-EVs show immense potential in AD therapy.

Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles

“…The precise modalities by which EVs infiltrate the NVU remain an area of intense research. It is posited that transcellular transport of EVs ensues via endocytic uptake by BMECs, an event capable of instigating phenotypic alterations within these cells and modulating the selective permeability of BBB [25,132,133]. This is exemplified by studies demonstrating that inducible pluripotent stem cell-derived small EVs (iPSC-sEVs) appear to counteract senescence in the BBB, offering cytoprotection in ischemic cerebrovascular insults [134].…”

Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney

“…These EVs can be engineered to express molecules that specifically target cancer cells, enhancing their therapeutic efficacy while minimizing off‐target effects. Additionally, MSC‐derived EVs can modulate the immune response against tumors, promoting antitumor immune activity and suppressing tumor‐induced immune evasion mechanisms (Yin et al, 2023; Zhu et al, 2023). As previously indicated, engineered MSCs or EVs derived from MSCs have been utilized for the purpose of inhibiting the proliferation and progression of urological cancer cells.…”

“…These EVs can be engineered to express molecules that specifically target cancer cells, enhancing their therapeutic efficacy while minimizing off-target effects. Additionally, MSC-derived EVs can modulate the immune response against tumors, promoting antitumor immune activity and suppressing tumor-induced immune evasion mechanisms (Yin et al, 2023;Zhu et al, 2023) The lentivirus expression system was employed to achieve stable overexpression of miR-138-5p in AD-SCs. Specifically, a lentivirus construct containing miR-138-5p or a negative control was generated and transfected into AD-SCs.…”

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

“…Nanotechnology integration with gene therapy offers a glimmer of hope to overcome the obstacles. , To develop siRNA and pDNA nanocarriers for BBB penetration and neuron-specific delivery, targeting ligand modification is a common strategy. ,− For instance, Shi et al designed galactose-modified stabilized siRNA nanoparticles to efficiently penetrate the BBB via Glut1 recycling, targeting BACE1 for AD therapy . Recently, exploring the combined delivery of targeted biomimetic carriers for efficient drug enrichment in brain tissue has been a hot point in drug delivery for brain diseases. , Mesenchymal stem cells (MSCs)-derived exosomes have the potential to promote tissue repair and nerve regeneration, and their surface, which is rich in transmembrane proteins and integrins, allows them to penetrate the BBB, thus making them a viable treatment for AD. − Recently, exosome-liposome hybrid nanovesicles have been generated based on membrane fusion technology, which is the next generation of drug delivery vehicles . By combining the endogenous targeting properties of exosomes with the drug delivery properties of artificial liposomes, this hybrid nanovesicle vector will enhance the circulating stability, better pharmacokinetic characteristics, and less immunogenicity of the vector in vivo. , Based on the above results, we anticipate the development of a biomimetic BBB-penetrable nanoparticle as a combined drug delivery system to enhance drug delivery efficiency for the synergistic gene treatment to prevent the production of oligomeric Aβ, regain microglia’s capability to phagocytose Aβ and accelerate to Aβ elimination, and eventually protected neurons.…”