Hydrophobicity of Lipid-Conjugated siRNAs Predicts Productive Loading to Small Extracellular Vesicles

Biscans, Annabelle; Haraszti, Reka A.; Echeverria, Dimas; Miller, Rachael; Didiot, Marie-Cécile; Nikan, Mehran; Roux, Loïc; Aronin, Neil; Khvorova, Anastasia

doi:10.1016/j.ymthe.2018.03.019

Cited by 37 publications

(40 citation statements)

References 60 publications

(83 reference statements)

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“…Initially, we and other researchers used external loading methods such as EV electroporation to directly incorporate siRNA into EVs (in the absence of cells), which were used as RNA delivery vehicles 32,37,39,59,60 . Nevertheless, the incorporation of large-sized mRNAs into EVs using internal methods (loading via cells) was not achieved previously.…”

Section: Discussionmentioning

confidence: 99%

Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells

et al. 2019

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RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratio between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells

et al. 2019

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“…They efficiently bind cellular membranes, enter cells, and stimulate gene silencing [ 53 , 54 , 154 ]. Exosomes are promising natural nano-devices for therapeutic RNA delivery but loading of the sufficient dose of RNAs remains a challenge [ 55 ]. To increase the efficiency, Bicans et al synthesized a group of cholesterol-conjugated hsiRNAs to be loaded into exosomes.…”

Section: Exosomes In Huntington’s Diseasementioning

confidence: 99%

Emerging Roles of Exosomes in Huntington’s Disease

Ananbeh

Vodička

Skalníková

2021

IJMS

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Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy.

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“…These surface modified EVs exhibited a 6-fold and 3-fold treatment efficacy in vitro and in vivo compared to unmodified PTX-loaded nanovesicles. For RNA delivery, the conjugation of siRNAs to cholesterol led to an increased loading efficiency demonstrating an exponential correlation between the hydrophobicity of the siRNA lipid conjugate and its EV-loading efficiency [ 94 ].…”

Section: Modification Of Isolated Evsmentioning

confidence: 99%

Engineered Extracellular Vesicles: Tailored-Made Nanomaterials for Medical Applications

et al. 2020

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Extracellular vesicles (EVs) are emerging as promising nanoscale therapeutics due to their intrinsic role as mediators of intercellular communication, regulating tissue development and homeostasis. The low immunogenicity and natural cell-targeting capabilities of EVs has led to extensive research investigating their potential as novel acellular tools for tissue regeneration or for the diagnosis of pathological conditions. However, the clinical use of EVs has been hindered by issues with yield and heterogeneity. From the modification of parental cells and naturally-derived vesicles to the development of artificial biomimetic nanoparticles or the functionalisation of biomaterials, a multitude of techniques have been employed to augment EVs therapeutic efficacy. This review will explore various engineering strategies that could promote EVs scalability and therapeutic effectiveness beyond their native utility. Herein, we highlight the current state-of-the-art EV-engineering techniques with discussion of opportunities and obstacles for each. This is synthesised into a guide for selecting a suitable strategy to maximise the potential efficacy of EVs as nanoscale therapeutics.

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Hydrophobicity of Lipid-Conjugated siRNAs Predicts Productive Loading to Small Extracellular Vesicles

Cited by 37 publications

References 60 publications

Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells

Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells

Emerging Roles of Exosomes in Huntington’s Disease

Engineered Extracellular Vesicles: Tailored-Made Nanomaterials for Medical Applications

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