Engineered extracellular vesicles as brain therapeutics

Lino, Miguel; Simões, Susana; Tomatis, Francesca; Albino, Inês; Barrera, Ángela; Vivien, Denis; Sobrino, Tomás; Ferreira, Lino

doi:10.1016/j.jconrel.2021.08.037

Cited by 41 publications

(27 citation statements)

References 145 publications

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“…Finally, how miR-146a crosses the BBB and activates brain TLR7 during sepsis warrants future study. Systemic administration of extracellular vesicles can influence CNS function ( Lino et al, 2021 ; Xin et al, 2013 ), suggesting a possible route of extracellular vehicles across the BBB and moving from the peripheral circulation to the CNS. Future direction of targeting extracellular vesicles as a miRNA cargo will be carefully investigated.…”

Section: Discussionmentioning

confidence: 99%

Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

Zou

et al. 2022

Brain, Behavior, and Immunity

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Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood–brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7 −/− mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3β signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation.

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Section: Discussionmentioning

confidence: 99%

Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

Zou

et al. 2022

Brain, Behavior, and Immunity

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“…The brain is one of the most important and most complex organs, serving as the center of the nervous system in the human body. Neurological impairments caused by traumatic brain injury (TBI) and different types of neurodegenerative diseases such as ischemia stroke, Alzheimer's disease, and Parkinson's disease in brain organs, are the major reasons for the long-term physical disability of adults, especially the increasing aged people, posing a considerable threat to public health 158 , 159 . Even worse, the treatment performance of traditional pharmacotherapy towards brain diseases has often been substantially compromised due to the presence of the blood-brain barrier, which makes it difficult for drugs to reach the brain lesions.…”

Section: Tissue Regeneration Applications Of Evs On Various Organsmentioning

confidence: 99%

Extracellular vesicles as bioactive nanotherapeutics: An emerging paradigm for regenerative medicine

Fang

Sun

et al. 2022

Theranostics

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In recent decades, extracellular vesicles (EVs), as bioactive cell-secreted nanoparticles which are involved in various physiological and pathological processes including cell proliferation, immune regulation, angiogenesis and tissue repair, have emerged as one of the most attractive nanotherapeutics for regenerative medicine. Herein we provide a systematic review of the latest progress of EVs for regenerative applications. Firstly, we will briefly introduce the biogenesis, function and isolation technology of EVs. Then, the underlying therapeutic mechanisms of the native unmodified EVs and engineering strategies of the modified EVs as regenerative entities will be discussed. Subsequently, the main focus will be placed on the tissue repair and regeneration applications of EVs on various organs including brain, heart, bone and cartilage, liver and kidney, as well as skin. More importantly, current clinical trials of EVs for regenerative medicine will also be briefly highlighted. Finally, the future challenges and insightful perspectives of the currently developed EV-based nanotherapeutics in biomedicine will be discussed. In short, the bioactive EV-based nanotherapeutics have opened new horizons for biologists, chemists, nanoscientists, pharmacists, as well as clinicians, making possible powerful tools and therapies for regenerative medicine.

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“…[ 149 ] When EVs are applied in vivo, there will also be some problems such as unclear biological distribution and poor functional tissue targeting capabilities. [ 150 ] In addition, regarding we still cannot guarantee the manufacturing scalability and purity of EVs. [ 151 ] Therefore, researchers have turned their attention to the engineering strategies of EVs to consolidate their inherent characteristics and promote their clinical translation.…”

Section: Engineering Strategies To Improve the Efficacy Of Tailored E...mentioning

confidence: 99%

Extracellular Vesicles in Tissue Engineering: Biology and Engineered Strategy

Pan

Sun

Chen

et al. 2022

Adv Healthcare Materials

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Extracellular vesicles (EVs), acting as an important ingredient of intercellular communication through paracrine actions, have gained tremendous attention in the field of tissue engineering (TE). Moreover, these nanosized extracellular particles (30-140 nm) can be incorporated into biomaterials according to different principles to facilitate signal delivery in various regenerative processes directly or indirectly. Bioactive biomaterials as the carrier will extend the retention time and realize the controlled release of EVs, which further enhance their therapeutic efficiency in tissue regeneration. Herein, the basic biological characteristics of EVs are first introduced, and then their outstanding performance in exerting direct impacts on target cells in tissue regeneration as well as indirect effects on promoting angiogenesis and regulating the immune environment, due to specific functional components of EVs (nucleic acid, protein, lipid, etc.), is emphasized. Furthermore, different design ideas for suitable EV-loaded biomaterials are also demonstrated. In the end, this review also highlights the engineered strategies, which aim at solving the problems related to natural EVs such as highly heterogeneous functions, inadequate tissue targeting capabilities, insufficient yield and scalability, etc., thus promoting the therapeutic pertinence and clinical potential of EV-based approaches in TE.

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Engineered extracellular vesicles as brain therapeutics

Cited by 41 publications

References 145 publications

Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis

Extracellular vesicles as bioactive nanotherapeutics: An emerging paradigm for regenerative medicine

Extracellular Vesicles in Tissue Engineering: Biology and Engineered Strategy

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