Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia

Peng, Boya; Yang, Yuqi; Wu, Zhiyuan; Tan, Rachel; Pham, Thach Tuan; Yeo, Eric; Pirisinu, Marco; Jayasinghe, Migara Kavishka; Pham, Tin Chanh; Liang, Kun; Shyh‐Chang, Ng; Le, Minh Tn

doi:10.1016/j.ymthe.2023.03.036

Cited by 14 publications

(3 citation statements)

References 39 publications

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“…The use of RBCEVs as a nanoparticulate carrier brings with it a host of advantages over synthetic nano formulations such as liposomes in terms of immunogenicity, toxicity, and biocompatibility. ,, We and other groups have previously demonstrated that RBCEVs are biocompatible, safe, nontoxic, nonimmunogenic and free of any cellular DNA, thus ensuring that the addition of this vector does not introduce any adverse effects. , Our data here also reflect that RBCEV-mediated delivery of ASOs is superior to the delivery of free ASOs or the REG1-ASO complex alone, substantiating the advantage of RBCEV-based ASO delivery. We also demonstrate that upon intratracheal administration, EVs are delivered directly to ACE2-positive epithelial cells in the lung, the primary site of SARS-CoV-2 infection, avoiding rapid clearance by macrophages of the reticuloendothelial system that is typically observed with intravenous administration.…”

Section: Discussionsupporting

confidence: 72%

Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy

Jayasinghe,

Gao,

Yap

et al. 2023

ACS Nano

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The COVID-19 pandemic has resulted in a large number of fatalities and, at present, lacks a readily available curative treatment for patients. Here, we demonstrate that unmodified red blood cell-derived extracellular vesicles (RBCEVs) can inhibit SARS-CoV-2 infection in a phosphatidylserine (PS) dependent manner. Using T cell immunoglobulin mucin domain-1 (TIM-1) as an example, we demonstrate that PS receptors on cells can significantly increase the adsorption and infection of authentic and pseudotyped SARS-CoV-2 viruses. RBCEVs competitively inhibit this interaction and block TIM-1-mediated viral entry into cells. We further extend the therapeutic efficacy of this antiviral treatment by loading antisense oligonucleotides (ASOs) designed to target conserved regions of key SARS-CoV-2 genes into RBCEVs. We establish that ASO-loaded RBCEVs are efficiently taken up by cells in vitro and in vivo to suppress SARS-CoV-2 replication. Our findings indicate that this RBCEV-based SARS-CoV-2 therapeutic displays promise as a potential treatment capable of inhibiting SARS-CoV-2 entry and replication.

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Section: Discussionsupporting

confidence: 72%

Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy

Jayasinghe,

Gao,

Yap

et al. 2023

ACS Nano

Self Cite

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“…EVs have also been explored as vehicles for drugs and therapeutic molecules in the context of cancer cachexia. Peng et al [26] demonstrated the efficacy of EV-mediated transportation of load for targeted therapy of cancer cachexia using red blood cellderived EVs (RBCEVs). The EVs were isolated from healthy human donors and used as carriers of small interference RNAs (siRNAs) targeting myostatin (Mstn) and malonyl-CoA dehydrogenase (Mlycd) mRNAs, both involved in skeletal muscle metabolism.…”

Section: Circulating Factors As Targets For Cancer Cachexia Treatmentmentioning

confidence: 99%

Circulating factors in cancer cachexia: recent opportunities for translational research

Coêlho,

de Aquino,

Santos

et al. 2024

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of review To discuss the recent discoveries and limitations of the available literature on emerging circulating biomarkers of cancer cachexia. Recent findings Studies on circulating factors in cancer cachexia show promising alternatives for diagnosing the syndrome in a minimally invasive manner in the clinic setting, as well as potential targets for cancer cachexia treatment. Factors secreted by the tumor and the adipose tissue, such as extracellular vesicles and soluble proteins, respectively, have been shown to either directly induce wasting in vitro and in vivo or to be altered in the cachectic phenotype. The detection and characterization of circulating cells allows detection of the precachectic stage and the levels of the soluble immune checkpoint protein programmed death ligand-1 (PD-L1) are correlated with the presence of the hallmarks of cancer cachexia. Summary Structural, molecular, and metabolic alterations have been observed in various tissues, revealing the occurrence of sustained inter-compartment crosstalk in cachectic patients. Early diagnosis of cancer cachexia becomes crucial to avoid the establishment of refractory cachexia through the implementation of interventions that may attenuate systemic inflammation and muscle loss. More studies on human cancer cachexia are required in order to address the recently discovered cachexia-associated circulating factors’ value as biomarkers of the syndrome.

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“…Of note, another source receiving great attention is red blood cells (RBCs) as they are readily available from the blood bank, thereby allowing large-scale EV production; additionally, they are enucleated cells devoid of DNA, causing no safety concern of horizontal gene transfer. 66 Le and coworkers has developed a strategy to generate scalable amounts of RBC-derived EVs for the delivery of therapeutic RNA drugs such as antisense oligonucleotides (ASOs), 67 siRNA, 68 and Cas9 messenger RNA 66 for cancer therapy with low cytotoxicity. The discussed cell sources and their characteristics are briefly summarized in Fig.…”

Section: Extracellular Vesicles For Cancer Therapymentioning

confidence: 99%

Genetically engineered cell-derived nanovesicles for cancer immunotherapy

He,

Zhao

2024

Nanoscale

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Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia

Cited by 14 publications

References 39 publications

Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy

Red Blood Cell-Derived Extracellular Vesicles Display Endogenous Antiviral Effects and Enhance the Efficacy of Antiviral Oligonucleotide Therapy

Circulating factors in cancer cachexia: recent opportunities for translational research

Genetically engineered cell-derived nanovesicles for cancer immunotherapy

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