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Page 196 Tutanov et al. Extracell Vesicles Circ Nucleic Acids 2023;4:195-217 https://dx.doi.org/10.20517/evcna.2023.17

INTRODUCTION
Cells release a dizzying array of EVs and nanoparticles, which differ in size, biogenesis, function, and cargo,
[1]
as has been recently reviewed by our group . In the present review, we have chosen to focus on three
subsets of EVs and nanoparticles: exosomes, exomeres, and supermeres, as they have the most relevance to
GPI-AP cargo. Exosomes, ranging in size from 40 - 150 nm, are a subset of lipid bilayer-enclosed small
extracellular vesicles (sEVs). They are defined as being of endocytic origin and containing tetraspanins,
[2,3]
CD9, CD63, and CD81 . Herein, we will use the more inclusive term, sEVs, unless the classic criteria for
exosomes are met. sEVs are increasingly recognized for their role in intercellular communication and their
[4,5]
cargo as potential diagnostic biomarkers and therapeutic targets . Over the years, numerous studies have
shown that sEVs play an important role in transferring functional proteins and nucleic acids in both health
and disease . They have been implicated in various oncogenic processes such as immunosuppression,
[6]
immune evasion, angiogenesis, epithelial-to-mesenchymal transition, establishment of a pro-tumorigenic
microenvironment and metastatic niche, and drug resistance [5,7,8] . The composition and content of sEVs can
reflect the status of the cell of origin, making the analysis of sEVs an area of interest for the development of
non-invasive diagnostic tools . In addition to their diagnostic potential, sEVs are also being studied as
[9]
therapeutic targets, with research exploring the possibility of blocking or modulating sEV release as a
strategy for cancer treatment . The recent discovery of exomeres and supermeres offers new opportunities
[10]
for further clinical exploration and translation [8,11] .

[11]
Exomeres, nanoparticles with a size range of 30 - 60 nm, were first described by Lyden et al. in 2017 and
are a relatively new addition to the collection of extracellular particles. Unlike EVs, exomeres are thought to
[11]
lack a double-lipid membrane, but they are associated with a unique set of RNAs and proteins . The
potential functions of exomeres are still being investigated, but they have been shown to play a role in
intercellular communication and regulation of cellular processes [12,13] . For example, exomeres have been
implicated in modulating signaling pathways, cell adhesion, and immune responses in recipient cells .
[13]

Supermeres, nanoparticles of an even smaller size than exomeres (25 - 35 nm), were first described in a
recent study from our lab and are another addition to the world of extracellular nanoparticles . First found
[13]
in a CRC cell line, supermeres are morphologically and structurally distinct from exomeres and have
different cellular uptake kinetics compared to sEVs and exomeres in vitro as well as greater uptake
in vivo . Supermeres have been found to contain high levels of clinically relevant proteins such as APP,
[13]
[13]
MET, GPC1, AGO2, and TGFBI, which were previously reported to be present in exosomes .
Furthermore, most of the extracellular RNA (exRNA) was found to be associated with supermeres rather
[13]
than sEVs and exomeres . There are concerns that similarities between exomeres and supermeres suggest a
continuum of nanoparticles only differing in size, but we contend that distinct differences in size, structure,
cargo, and biological properties warrant their separate classification at this time . Therefore, we propose
[14]
that exosomes, exomeres, and supermeres are distinct subtypes of circulating EVs and nanoparticles
(EVPs). By examining these subtypes as separate entities, we can gain a more complete understanding of
EVP biogenesis, their individual biological effects, and the overall interplay, which can be more easily
achieved now after our publication of comprehensive isolation method of EVs, exomeres, and supermeres
from the same stating material . These discoveries can translate to elucidating the roles these secreted
[15]
particles play in remodeling the tumor microenvironment, invasion, immune suppression, and other
processes that are important for colorectal carcinogenesis.