Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery

Pham, Tin Chanh; Jayasinghe, Migara Kavishka; Pham, Thach Tuan; Yang, Yuqi; Wei, Likun; Usman, Waqas Muhammad; Chen, Huan; Pirisinu, Marco; Gong, Jing; Kim, Seongkyeol; Peng, Boya; Wang, Weixi; Chan, Charlene; Ma, Victor; Nguyen, Nhung T.; Kappei, Dennis; Nguyen, Xuan‐Hung; Cho, William C.; Shi, Jiahai; Le, Minh Vuong

doi:10.1002/jev2.12057

Cited by 109 publications

(100 citation statements)

References 37 publications

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“…Novel formats such as nanobodies with favorable biophysical properties, offer opportunities to mitigate certain drug discovery risks (5,30). Innovative approaches for targeted delivery of nanobody-based therapeutics are being pursued currently (31).…”

Section: Discussionmentioning

confidence: 99%

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INDI – Integrated Nanobody Database for Immunoinformatics

Deszyński¹,

Młokosiewicz²,

Volanakis

et al. 2021

Preprint

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Nanobodies, a subclass of antibodies found in camelids, are a versatile molecular binding scaffold composed of a single polypeptide chain. The small size of nanobodies bestows multiple therapeutic advantages (stability, tumor penetration) with the first therapeutic approval in 2018 cementing the clinical viability of this format. Structured data and sequence information of nanobodies will enable the accelerated clinical development of nanobody-based therapeutics. Though the nanobody sequence and structure data are deposited in the public domain at an accelerating pace, the heterogeneity of sources and lack of standardization hampers reliable harvesting of nanobody information. We address this issue by creating the Integrated Database of Nanobodies for Immunoinformatics (INDI, http://research.naturalantibody.com/nanobodies). INDI collates nanobodies from all the major public outlets of biological sequences: patents, GenBank, next-generation sequencing repositories, structures and scientific publications. We equip INDI with powerful nanobody-specific sequence and text search facilitating access to more than 11 million nanobody sequences. INDI should facilitate development of novel nanobody-specific computational protocols helping to deliver on the therapeutic promise of this drug format.

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Section: Discussionmentioning

confidence: 99%

“…Besides the molecular therapies (31), nanobodies are being used in the development of several cellular therapies (31)(32)(33)(34)(35). Developing nanobody therapies using traditional lab-based approaches still carries an overhead of many years of experimentation before they reach the clinic.…”

Section: Discussionmentioning

confidence: 99%

INDI – Integrated Nanobody Database for Immunoinformatics

Deszyński¹,

Młokosiewicz²,

Volanakis

et al. 2021

Preprint

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“…35 To test the cellular uptake of ASO-RBCEVs, Cy5-labeled ASO3.2 was loaded into RBCEVs that were labeled with carboxyfluorescein succinimidyl ester (CFSE), which fluoresces only in the presence of esterase when they are either loaded into RBCEVs or internalized into cells. 36 Upon treatment with Cy5-ASO loaded into CFSE-RBCEVs, 100% of KYSE510 cells were Cy5 and CFSE double positive, indicating a very high cellular uptake of ASO-RBCEVs (Figure 6D). Next, mice were injected with untreated KYSE510 cells subcutaneously for tumor development, followed by administration of ASO-RBCEVs or naked (unloaded) ASO intratumorally every 4 days (Figure 6E).…”

Section: Aso32 Effectively Inhibits Tumor Incidence and Growth In Vivomentioning

confidence: 98%

Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer

et al. 2021

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Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3 0 end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2 0 -O-methyl (2 0 -O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.

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“…Pham et al developed a simple enzymatic method to bind peptides and nanobodies to EVs via covalent bonds without genetic or chemical modifications [ 109 ]. The authors used the enzymes sortase A and OaAEP1 ligase to bind proteins of interest to the surface of erythrocyte-derived EVs.…”

Section: Tumor-targeting Evsmentioning

confidence: 99%

Challenges for the Development of Extracellular Vesicle-Based Nucleic Acid Medicines

Kuriyama

Yoshioka

Kikuchi

et al. 2021

Cancers

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Nucleic acid drugs, such as siRNAs, antisense oligonucleotides, and miRNAs, exert their therapeutic effects by causing genetic changes in cells. However, there are various limitations in their delivery to target organs and cells, making their application to cancer treatment difficult. Extracellular vesicles (EVs) are lipid bilayer particles that are released from most cells, are stable in the blood, and have low immunogenicity. Methods using EVs to deliver nucleic acid drugs to target organs are rapidly being developed that take advantage of these properties. There are two main methods for loading nucleic acid drugs into EVs. One is to genetically engineer the parent cell and load the target gene into the EV, and the other is to isolate EVs and then load them with the nucleic acid drug. Target organ delivery methods include passive targeting using the enhanced permeation and retention effect of EVs and active targeting in which EVs are modified with antibodies, peptides, or aptamers to enhance their accumulation in tumors. In this review, we summarize the advantages of EVs as a drug delivery system for nucleic acid drugs, the methods of loading nucleic acid drugs into EVs, and the targeting of EVs to target organs.

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Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery

Cited by 109 publications

References 37 publications

INDI – Integrated Nanobody Database for Immunoinformatics

INDI – Integrated Nanobody Database for Immunoinformatics

Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer

Challenges for the Development of Extracellular Vesicle-Based Nucleic Acid Medicines

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