New approaches in extracellular vesicle engineering for improving the efficacy of anti-cancer therapies

Jayasinghe, Migara Kavishka; Tan, Melissa; Peng, Boya; Yang, Yuqi; Sethi, Gautam; Pirisinu, Marco; Le, Minh Tn

doi:10.1016/j.semcancer.2021.02.010

Cited by 32 publications

(27 citation statements)

References 146 publications

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“…Surface functionalization aims to improve the pharmacokinetics of EVs, actively directing EVs to desired cells via targeting moieties immobilized on the EV surface, as well as by decreasing non-specific uptake or delaying phagocytic clearance. The combination of these strategies can decrease the onset of side effects, while allowing targeting EVs to be efficiently internalized by diseased cells, bypassing cellular barriers through natural endocytic processes 4 .…”

Section: Introductionmentioning

confidence: 99%

“…While popular approaches based on parental cell transfection and lipid insertion have been widely utilized by multiple groups to engineer the surface of EVs, these approaches present certain limitations that hinder their successful clinical translation. Some of the major concerns associated with existing methods include the risk of mutagenic nucleic acid transfer from parental cells that are frequently transduced using viruses, the transient nature of lipid insertion and the ability of certain chemical-based methods to compromise or alter the EVs' endogenous properties 4 . There are also concerns regarding the scalability and reproducibility of these approaches, given the tedious and costly nature of EV isolation, a barrier not encountered by synthetic liposomal formulations 5 .…”

Section: Introductionmentioning

confidence: 99%

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Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy

Jayasinghe¹,

Pirisinu²,

Yang³

et al. 2022

Theranostics

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy

Jayasinghe¹,

Pirisinu²,

Yang³

et al. 2022

Theranostics

Self Cite

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“…Unmodified EVs have some disadvantages such as targeted insufficient, poor stability, low delivery efficiency and efficacy. In order to overcome these deficiencies, researchers designed some ideal functionalization strategies for engineered EVs according to specific pathogenic mechanisms and corresponding diseases (Jayasinghe et al., 2021 ). According to the differences in the antitumor molecules carried by EVs and the different methods of engineering EVs, the application of EVs in tumor therapy can be divided into the following two categories: engineered EVs via cell modification, direct modification of EVs.…”

Section: Functionalization Strategy Of Evsmentioning

confidence: 99%

Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy

et al. 2022

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Increasing evidences show that unmodified extracellular vesicles (EVs) derived from various cells can effectively inhibit the malignant progression of different types of tumors by delivering the bioactive molecules. Therefore, EVs are expected to be developed as emerging anticancer drugs. Meanwhile, unmodified EVs as an advanced and promising nanocarrier that is frequently used in targeted delivery therapeutic cargos and personalized reagents for the treatment and diagnosis of cancer. To improve the efficacy of EV-based treatments, researchers are trying to engineering EVs as an emerging nanomedicine translational therapy platform through biological, physical and chemical approaches, which can be broaden and altered to enhance their therapeutic capability. EVs loaded with therapeutic components such as tumor suppressor drugs, siRNAs, proteins, peptides, and conjugates exhibit significantly enhanced anti-tumor effects. Moreover, the design and preparation of tumor-targeted modified EVs greatly enhance the specificity and effectiveness of tumor therapy, and these strategies are expected to become novel ideas for tumor precision medicine. This review will focus on reviewing the latest research progress of functionalized EVs, clarifying the superior biological functions and powerful therapeutic potential of EVs, for researchers to explore new design concepts based on EVs and build next-generation nanomedicine therapeutic platforms.

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“…MSC-exosomes could hold the homing ability of native MSCs toward an inflammation site [164]. Their natural origin will confer a biocompatible profile while the specific protein pattern on the surface of MSC-exosomes will favor innate organotropic homing [165]. Being nanomaterials, the exosomes from MSCs can be delivered by biomaterials, promoting broader therapeutic effects in regeneration approaches or in vivo controlled delivery.…”

Section: Antibacterial Exosomes As Future Biomedicinesmentioning

confidence: 99%

Microfluidic Tools for Enhanced Characterization of Therapeutic Stem Cells and Prediction of Their Potential Antimicrobial Secretome

Marrazzo

Pizzuti

Zia³

et al. 2021

Antibiotics

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Antibiotic resistance is creating enormous attention on the development of new antibiotic-free therapy strategies for bacterial diseases. Mesenchymal stromal stem cells (MSCs) are the most promising candidates in current clinical trials and included in several cell-therapy protocols. Together with the well-known immunomodulatory and regenerative potential of the MSC secretome, these cells have shown direct and indirect anti-bacterial effects. However, the low reproducibility and standardization of MSCs from different sources are the current limitations prior to the purification of cell-free secreted antimicrobial peptides and exosomes. In order to improve MSC characterization, novel label-free functional tests, evaluating the biophysical properties of the cells, will be advantageous for their cell profiling, population sorting, and quality control. We discuss the potential of emerging microfluidic technologies providing new insights into density, shape, and size of live cells, starting from heterogeneous or 3D cultured samples. The prospective application of these technologies to studying MSC populations may contribute to developing new biopharmaceutical strategies with a view to naturally overcoming bacterial defense mechanisms.

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New approaches in extracellular vesicle engineering for improving the efficacy of anti-cancer therapies

Cited by 32 publications

References 146 publications

Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy

Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy

Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy

Microfluidic Tools for Enhanced Characterization of Therapeutic Stem Cells and Prediction of Their Potential Antimicrobial Secretome

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