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A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

ABSTRACT: Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.

SUBMITTER: Dooley K

PROVIDER: S-EPMC8116569 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

Dooley Kevin K McConnell Russell E RE Xu Ke K Lewis Nuruddeen D ND Haupt Sonya S Youniss Madeleine R MR Martin Shelly S Sia Chang Ling CL McCoy Christine C Moniz Raymond J RJ Burenkova Olga O Sanchez-Salazar Jorge J Jang Su Chul SC Choi Bryan B Harrison Rane A RA Houde Damian D Burzyn Dalia D Leng Charan C Kirwin Katherine K Ross Nikki L NL Finn Jonathan D JD Gaidukov Leonid L Economides Kyriakos D KD Estes Scott S Thornton James E JE Kulman John D JD Sathyanarayanan Sriram S Williams Douglas E DE

Molecular therapy : the journal of the American Society of Gene Therapy 20210121 5

Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragment ...[more]

PMID: 33484965

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Project description:The advent of novel therapeutics in recent years has urged the need for a safe, non-immunogenic drug delivery vector capable of delivering therapeutic payloads specifically to diseased cells, thereby increasing therapeutic efficacy and reducing side effects. Extracellular vesicles (EVs) have garnered attention in recent years as a potentially ideal vector for drug delivery, taking into account their intrinsic ability to transfer bioactive cargo to recipient cells and their biocompatible nature. However, natural EVs are limited in their therapeutic potential and many challenges need to be overcome before engineered EVs satisfy the levels of efficiency, stability, safety and biocompatibility required for therapeutic use. Here, we demonstrate that an enzyme-mediated surface functionalization method in combination with streptavidin-mediated conjugation results in efficient surface functionalization of EVs. Surface functionalization using the above methods permits the stable and biocompatible conjugation of peptides, single domain antibodies and monoclonal antibodies at high copy number on the EV surface. Functionalized EVs demonstrated increased accumulation in target cells expressing common cancer associated markers such as CXCR4, EGFR and EpCAM both in vitro and in vivo. The functionality of this approach was further highlighted by the ability of targeting EVs to specifically deliver therapeutic antisense oligonucleotides to a metastatic breast tumor model, resulting in increased knockdown of a targeted oncogenic microRNA and improved metastasis suppression. The method was also used to equip EVs with a bifunctional peptide that targets EVs to leukemia cells and induces apoptosis, leading to leukemia suppression. Moreover, we conducted extensive testing to verify the biocompatibility, and safety of engineered EVs for therapeutic use, suggesting that surface modified EVs can be used for repeated dose treatment with no detectable adverse effects. This modular, biocompatible method of EV engineering offers a promising avenue for the targeted delivery of a range of therapeutics while addressing some of the safety concerns associated with EV-based drug delivery.

Dataset Information

A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

Publications

A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

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