Supermeres are functional extracellular nanoparticles replete with disease biomarkers and therapeutic targets

Abstract

Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer’s disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.

Exploration of Extracellular Vesicle miRNAs, Targeted mRNAs and Pathways in Prostate Cancer: Relation to Disease Status and Progression

“…These steps attempt to remove miRNA in other carriers than EV or miRNA associated with the molecular corona on the EV surface [23,27,74,75]. Our detected miRNAs can therefore be located in or on EV or in other small-sized miRNA carriers remaining in the samples, including recently identified supermeres [27,76]. Other limitations of the study include relatively small sample numbers in the individual groups, which affects statistical power, and modest fold changes for some miRNAs.…”

Electrodeposited Magnetic Nanoporous Membrane (MNM) with a Multi-Edge Superparamagnetic Heterogeneous Wedge Junction for High-Yield and High-Throughput Immunocapture of Specific Extracellular Vesicles and Lipoproteins

“…In this study, EVs were first isolated from from human colorectal cancer cells (DiFi) by ANM (asymetrical nanoporous membrane). Then specific EVs with EGFR membrane proteins were isolated by the MNM to accurately quantify the miRNA content of specific EVs.Based on analysis of EGFR-containing DiFi EVs, isolated EVs were likely exosomes based on tetraspanin content 34 . Some of the EVs released by the DiFi cells exhibited inactive EGFR and active EGFR 34 .…”

“…Then specific EVs with EGFR membrane proteins were isolated by the MNM to accurately quantify the miRNA content of specific EVs.Based on analysis of EGFR-containing DiFi EVs, isolated EVs were likely exosomes based on tetraspanin content 34 . Some of the EVs released by the DiFi cells exhibited inactive EGFR and active EGFR 34 . We utilized a total EGFR antibody that captures both active and inactive EGFR in this experiment.…”

Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases

“…The term “extracellular vesicles” refers to particles naturally released from the cell that do not contain a functional nucleus, i.e., they cannot replicate themselves ( Johnstone, 2005 ). Extracellular vesicles (EVs) are released by most cell types and can be classified into different subtypes, including large and small extracellular vesicles (respectively, lEVs and sEVs), exomeres, supermeres, oncosomes, and apoptotic bodies ( El Andaloussi et al, 2013 ; Brites, 2020 ; Zhang et al, 2021 ). These EVs are different in size, density, biochemical and biophysical properties, as well as in secretion pathways, which may depend on the donor cells that produce them ( Figure 1 ).…”

“…Nucleic acids and lipids are also reported as part of exomeres’ cargo. Lately, supermeres, nanoparticles smaller than sEVs and exomeres, and morphologically distinct from exomeres, were described to be easily ingested and enriched with cargo involved in several cancers, as well as Alzheimer’s and cardiovascular diseases ( Zhang et al, 2021 ). They are enriched in proteins and miRNAs, as well as miRNA-processing proteins such as Argonaute RISC Catalytic Component 2 (AGO2), and are functional agents of intercellular communication, also constituting candidate biomarkers and therapeutic targets ( Clancy et al, 2021 ).…”