Osteoclast-targeted delivery of anti-miRNA oligonucleotides by red blood cell extracellular vesicles

Xu, Limei; Xu, Xiao; Liang, Yujie; Wen, Caining; Ouyang, Kan; Huang, Jiadai; Xiao, Yin; Deng, Xin; Xia, Jiang; Duan, Li

doi:10.1016/j.jconrel.2023.04.043

Cited by 38 publications

(17 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Infrapatellar fat pad (IPFP)-derived MSCs promoted the proliferation of chondrocytes and synthesis of extracellular matrix and reduced expression of catabolic factors to prevent cartilage damage and relieve walking disability 44 . Xu et al reported anti-mRNA delivery by red blood cell-derived engineered EVs to osteoclasts as a potential novel treatment of osteoporosis 45 . The red blood cell-derived engineered EVs were genetically modified to express a bi-functional fusion protein of TRAP-binding protein and a viral protein CP05 to guide the targeted delivery to osteoclast 45 .…”

Section: Discussionmentioning

confidence: 99%

“…Xu et al reported anti-mRNA delivery by red blood cell-derived engineered EVs to osteoclasts as a potential novel treatment of osteoporosis 45 . The red blood cell-derived engineered EVs were genetically modified to express a bi-functional fusion protein of TRAP-binding protein and a viral protein CP05 to guide the targeted delivery to osteoclast 45 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Small extracellular vesicles (sEVs)-based gene delivery platform for cell-specific CRISPR/Cas9 genome editing

Dubey,

Chen,

Jiang

et al. 2024

Theranostics

View full text Add to dashboard Cite

Small extracellular vesicles (sEVs) are naturally occurring vesicles that have the potential to be manipulated to become promising drug delivery vehicles for on-demand in vitro and in vivo gene editing. Here, we developed the modular safeEXO platform, a prototype sEV delivery vehicle that is mostly devoid of endogenous RNA and can efficaciously deliver RNA and ribonucleoprotein (RNP) complexes to their intended intracellular targets manifested by downstream biologic activity. We also successfully engineered producer cells to produce safeEXO vehicles that contain endogenous Cas9 (safeEXO-CAS) to effectively deliver efficient ribonucleoprotein (RNP)-mediated CRISPR genome editing machinery to organs or diseased cells in vitro and in vivo . We confirmed that safeEXO-CAS sEVs could co-deliver ssDNA, sgRNA and siRNA, and efficaciously mediate gene insertion in a dose-dependent manner. We demonstrated the potential to target safeEXO-CAS sEVs by engineering sEVs to express a tissue-specific moiety, integrin alpha-6 (safeEXO-CAS-ITGA6), which increased their uptake to lung epithelial cells in vitro and in vivo . We tested the ability of safeEXO-CAS-ITGA6 loaded with EMX1 sgRNAs to induce lung-targeted editing in mice, which demonstrated significant gene editing in the lungs with no signs of morbidity or detectable changes in immune cell populations. Our results demonstrate that our modular safeEXO platform represents a targetable, safe, and efficacious vehicle to deliver nucleic acid-based therapeutics that successfully reach their intracellular targets. Furthermore, safeEXO producer cells can be genetically manipulated to produce safeEXO vehicles containing CRISPR machinery for more efficient RNP-mediated genome editing. This platform has the potential to improve current therapies and increase the landscape of treatment for various human diseases using RNAi and CRISPR approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Small extracellular vesicles (sEVs)-based gene delivery platform for cell-specific CRISPR/Cas9 genome editing

Dubey,

Chen,

Jiang

et al. 2024

Theranostics

View full text Add to dashboard Cite

show abstract

“… 165 Studies have shown that miRNA expression is dysregulated in cancers and other diseases. 166 Therefore, altering the miRNA levels in target cells has the potential to serve as a therapeutic intervention. 165 miRNA wrapped in EVs for systemic drug delivery can well-solve currently existing problems facing the miRNA delivery field (such as low miRNA targeting, high toxicity, poor delivery, and rapid degradation).…”

Section: Evs As Gene Drug Delivery Vehiclesmentioning

confidence: 99%

Extracellular Vesicles: A New Star for Gene Drug Delivery

Sun,

Zhang,

Liu

et al. 2024

IJN

View full text Add to dashboard Cite

Recently, gene therapy has become a subject of considerable research and has been widely evaluated in various disease models. Though it is considered as a stand-alone agent for COVID-19 vaccination, gene therapy is still suffering from the following drawbacks during its translation from the bench to the bedside: the high sensitivity of exogenous nucleic acids to enzymatic degradation; the severe side effects induced either by exogenous nucleic acids or components in the formulation; and the difficulty to cross the barriers before reaching the therapeutic target. Therefore, for the successful application of gene therapy, a safe and reliable transport vector is urgently needed. Extracellular vesicles (EVs) are the ideal candidate for the delivery of gene drugs owing to their low immunogenicity, good biocompatibility and low toxicity. To better understand the properties of EVs and their advantages as gene drug delivery vehicles, this review covers from the origin of EVs to the methods of EVs generation, as well as the common methods of isolation and purification in research, with their pros and cons discussed. Meanwhile, the engineering of EVs for gene drugs is also highlighted. In addition, this paper also presents the progress in the EVs-mediated delivery of microRNAs, small interfering RNAs, messenger RNAs, plasmids, and antisense oligonucleotides. We believe this review will provide a theoretical basis for the development of gene drugs.

show abstract

“…The CP05 peptide, identified by phage display, enables the targeting and capture of exosomes from diverse origins by binding to CD63 . In our previous study, we employed CP05-coupled TRAP-binding peptide (TBP), a bifunctional peptide, TBP-CP05, which binds to CD63 on RBCEVs and receptors on osteoclasts, and used RBCEVs as a carrier to achieve the targeting of osteoclasts for the delivery of anti-miR-214 for the treatment of osteoporosis . CD63 is a protein with four transmembrane domains enriched on the surface of exosomes and is regarded as an exosomal marker .…”

Section: Introductionmentioning

confidence: 99%

“…17 In our previous study, we employed CP05coupled TRAP-binding peptide (TBP), a bifunctional peptide, TBP-CP05, which binds to CD63 on RBCEVs and receptors on osteoclasts, and used RBCEVs as a carrier to achieve the targeting of osteoclasts for the delivery of anti-miR-214 for the treatment of osteoporosis. 18 CD63 is a protein with four transmembrane domains enriched on the surface of exosomes and is regarded as an exosomal marker. 19 However, due to the heterogeneity of EVs, the expression level of CD63 in EVs from different sources is unstable, e.g., very low in EVs from human plasma.…”

Section: ■ Introductionmentioning

confidence: 99%

Phage Display Screening of Anchor Peptides for Red Blood Cell-Derived Extracellular Vesicles

Xu,

Xia

et al. 2024

ACS Omega

Self Cite

View full text Add to dashboard Cite

Extracellular vesicles (EVs) are increasingly used for disease diagnosis and treatment. Among them, red blood cellderived EVs (RBC-EVs) have attracted great attention due to their abundant sources and low risks of gene transfer (RBC-EVs lack nuclear and mitochondrial DNA). Here, we first revealed the high expression level of membrane protein solute carrier family 4 member 1 (SLC4A1) in RBC-EVs through proteomic analysis. We then identified several binding peptides with high affinity for the SLC4A1 extracellular domain (SLC4A1-EC) from phage display library screening. A high affinity of SLC4A1-EC and the three peptides (XRB2, XRE4, and XRH7) were assessed in vitro using surface plasmon resonance analysis and SDS−polyacrylamide gel electrophoresis (SDS−PAGE). The binding sites of SLC4A1-EC and polypeptides were further predicted by LigPlot + analysis, and the results showed that these three polypeptides could bind to part of the hydrophobic residues of SLC4A1-EC. The binding efficiency of the anchor peptides to the RBC-EVs was further verified by flow cytometry and fluorescence imaging. In conclusion, we successfully screened three specific RBC-EV-targeting peptides which could potentially be utilized for isolating RBC-derived EVs from serum samples. More importantly, this peptide could be coupled with targeting peptides to modify RBC-EVs for drug delivery. Our work will provide a viable method for optimizing the function of RBC-EVs.

show abstract

Osteoclast-targeted delivery of anti-miRNA oligonucleotides by red blood cell extracellular vesicles

Cited by 38 publications

References 60 publications

Small extracellular vesicles (sEVs)-based gene delivery platform for cell-specific CRISPR/Cas9 genome editing

Small extracellular vesicles (sEVs)-based gene delivery platform for cell-specific CRISPR/Cas9 genome editing

Extracellular Vesicles: A New Star for Gene Drug Delivery

Phage Display Screening of Anchor Peptides for Red Blood Cell-Derived Extracellular Vesicles

Contact Info

Product

Resources

About