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Stem Cell-derived Extracellular Vesicles: A Promising Nano Delivery Platform to the Brain?

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Abstract

A very important cause of the frustration with drug therapy for central nervous system (CNS) diseases is the failure of drug delivery. The blood–brain barrier (BBB) prevents most therapeutic molecules from entering the brain while maintaining CNS homeostasis. Scientists are keen to develop new brain drug delivery systems to solve this dilemma. Extracellular vesicles (EVs), as a class of naturally derived nanoscale vesicles, have been extensively studied in drug delivery due to their superior properties. This review will briefly present current brain drug delivery strategies, including invasive and non-invasive techniques that target the brain, and the application of nanocarriers developed for brain drug delivery in recent years, especially EVs. The cellular origin of EVs affects the surface protein, size, yield, luminal composition, and other properties of EVs, which are also crucial in determining whether EVs are useful as drug carriers. Stem cell-derived EVs, which inherit the properties of parental cells and avoid the drawbacks of cell therapy, have always been favored by researchers. Thus, in this review, we will focus on the application of stem cell-derived EVs for drug delivery in the CNS. Various nucleic acids, proteins, and small-molecule drugs are loaded into EVs with or without modification and undergo targeted delivery to the brain to achieve their therapeutic effects. In addition, the challenges facing the clinical application of EVs as drug carriers will also be discussed. The directions of future efforts may be to improve drug loading efficiency and precise targeting.

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Abbreviations

AD:

Alzheimer’s disease

ADMSCs:

Adipose-derived mesenchymal stem cells

ADSCs:

Adipose-derived stem cells

AMT:

Adsorptive-mediated transcytosis

Axin2:

Axis inhibition protein 2

Aβ:

β-Amyloid

BBB:

Blood-brain barrier

BECs:

Brain endothelial cells

BMSCs:

Bone marrow mesenchymal stem cells

CCL-2:

C-C chemokine ligand 2

CCR-2:

C-C chemokine receptor type 2

CED:

Convection enhanced delivery

CMT:

Carrier-mediated transport

CNS:

Central nervous system

CPP:

Cell-penetrating peptide

CXCR4:

CXC motif chemokine receptor type 4

DALYs:

Disability-adjusted life-years

DLS:

Dynamic light scattering

ECs:

Endothelial cells

EPCs:

Endothelial progenitor cells

ESCs:

Embryonic stem cells

EVs:

Extracellular vesicles

5-FC:

5-Fluorocytosine

FDA:

US Food and Drug Administration

FUS:

Focused ultrasound

GBM:

Glioblastoma multiforme

GCV:

Ganciclovir

GSCs:

Glioma stem cells

HD:

Huntington’s disease

hiPSCs:

Human induced pluripotent stem cells

HMOX1:

Heme oxygenase-1

HSCs:

Hematopoietic stem cells

HSSP:

HMOX1-specific short peptide

HSVTK:

Herpes simplex virus thymidine kinase

HTT:

Huntingtin

iPSCs:

Induced pluripotent stem cells

ISEV:

International Society for Extracellular Vesicles

MCAO:

Middle cerebral artery occlusion

MPS:

Mononuclear phagocytic system

MRgFUS:

Magnetic resonant–guided focused ultrasound

MSCs:

Mesenchymal stem cells

MSC-EVs:

MSC-derived EVs

MT:

Mechanical thrombectomy

NFT:

Neurofibrillary tangles

NLCs:

Nanostructured lipid carriers

NPs:

Nanoparticles

NSCs:

Neural stem cells

NTA:

Nanoparticle tracking analysis

PBCA:

Poly(butylcyanoacrylate)

PD:

Parkinson’s disease

PEDF:

Pigment epithelium-derived factor

PEG:

Polyethylene glycol

PLGA:

Poly(lactic-co-glycolic acid)

PNPs:

Polymeric nanoparticles

PSCI:

Post-stroke cognitive impairment

PTX:

Paclitaxel

RMT:

Receptor-mediated transcytosis

RVG:

Rabies virus glycoprotein

SCs:

Stem cells

SEC:

Size exclusion chromatography

sEVs:

Small extracellular vesicles

siRNA:

Small interfering RNA

SPION:

Superparamagnetic iron oxide nanoparticles

TfR:

Transferrin receptor

TJ:

Tight junction

TMZ:

Temozolomide

tPAs:

Tissue plasminogen activators

yCD::UPRT:

Yeast cytosine deaminase (CD)::uracil phosphoribosyl transferase fusion gene

Zeb2:

Zinc finger E-box binding homeobox 2 protein

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81774059), the Tianjin Natural Science Foundation (No. 19JCZDJC37100)

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National Natural Science Foundation of China (No. 81774059); Tianjin Natural Science Foundation (No. 19JCZDJC37100).

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  1. Yuying Guo and Dongsheng Hu contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China

    Yuying Guo, Lu Lian, Linna Zhao & Shixin Xu

  2. Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, 300193, China

    Yuying Guo, Linna Zhao & Shixin Xu

  3. National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China

    Yuying Guo, Lu Lian, Linna Zhao & Shixin Xu

  4. Graduate School, Tianjin Medical University, Tianjin, 300070, China

    Dongsheng Hu & Mingli Li

  5. Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China

    Lu Lian

  6. Integrative Medical Diagnosis Laboratory, Tianjin Nankai Hospital, Tianjin, 300100, China

    Huijing Bao

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Contributions

All authors contributed to the study conception and design. Yuying Guo, Dongsheng Hu and Mingli Li performed the literature search. The first draft of the manuscript was written by Yuying Guo and Dongsheng Hu. Lu Lian, Linna Zhao and Yuying Guo drew the figures. Shixin Xu and Huijing Bao critically revised the work. All authors read and approved the final manuscript.

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Guo, Y., Hu, D., Lian, L. et al. Stem Cell-derived Extracellular Vesicles: A Promising Nano Delivery Platform to the Brain?. Stem Cell Rev and Rep 19, 285–308 (2023). https://doi.org/10.1007/s12015-022-10455-4

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