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dependent manner and which are involved in signaling through the non-canonical intercellular Notch
signaling pathway [4,15] . In turn, supramolecular attack particles (SMAPs) are immune system-specific
particles of approximately 120 nm secreted by cytotoxic T lymphocytes, which deliver proteins, such as
[5]
perforins and granzymes, to target cells and have autonomous cytotoxicity . Mitovesicles are small EVPs
isolated from brain tissue that are rich in mitochondrial proteins, lipids, and DNA, and have been
[6]
implicated in mitochondrial abnormalities associated with Down syndrome . Large oncosomes are vesicles
1-10 µm in size shed by tumor cells that promote tumor progression [9,10] . Exophers are 4 µm-sized vesicles
secreted from nematode (C. elegans) neurons containing proteins and organelles that are secreted as a type
of cellular stress response to maintain cellular proteostasis . Taken together, these findings demonstrate
[11]
that EVPs exhibit diversity not only in size, but also in their origin, targets, and functions. Since some of
these categories overlap or are not fully defined, and in response to the increasing number of EVP subsets,
the International Society for Extracellular Vesicles (ISEV) has established the Minimal Information for
Studies of Extracellular Vesicles (MISEV) guidelines to provide a standardized set of reporting criteria for
characterizing EVPs . The classification of EVPs is still evolving, and international consensus is being
[16]
discussed and updated.

Although much remains unknown regarding the biogenesis, target cells and organs, as well as the function
of newly identified EVPs, ongoing research suggests that these properties may also be unique to each EVP
subset. Additionally, EVPs may possess yet-to-be-defined physiological and pathological functions that
transcend the limits of conventional classification, highlighting their highly diverse nature and central roles
in intercellular communication throughout the animal kingdom and evolution.

EVP ROLES IN INTERCELLULAR COMMUNICATION
As an intercellular communication system, EVPs may be the most complex, as they can horizontally
transfer a wide range of biomolecules to target cells. As a result, EVPs are essential means of information
transfer in a wide range of physiological processes, such as immunity, neurology, tissue regeneration, and
development, as well as pathological processes, such as cancer, inflammation, infection, neurological
diseases, cardiovascular and metabolic diseases, and autoimmune diseases [17-19] . Thus, while EVPs are
involved in communication between various cells during normal development and physiology, their best-
characterized functions are in cancer. As such, EVPs can transfer information between cancer cells and
immune cells, epithelial cells, stromal cells, neurons, and even pathogens [17-19] . Pioneering studies in the late
2000s demonstrated that intercellular communication occurs via the transfer of EVP content [20-22] . For
example, del Conde et al. showed that tissue factors in EVPs derived from monocytes or macrophages are
transferred to platelets and activate the coagulation process, while Ratajczak et al. showed that EVPs derived
from embryonic stem cells are enriched in transcription factor mRNA, which can be delivered to target cells
and translated into the corresponding proteins [20,21] . The biomolecules delivered by EVPs, including
proteins, RNA (mRNA, miRNA, long non-coding RNA), DNA, lipids, and metabolites, can have various
effects on target cells and can modify their characteristics [23-25] . This horizontal transfer of information
through EVPs occurs not only locally but also systemically, as EVPs can deliver biomolecules to distant
organs. For example, EVPs derived from melanoma can transfer the Met oncoprotein to progenitor cells in
the bone marrow, reprogramming them and leading to their egress from the bone marrow and migration to
future sites of metastasis where they contribute to pre-metastatic niche formation . Moreover,
[25]
biomolecules delivered by EVPs exert various effects on target cells, ranging from direct and short-term
effects through the transfer of molecules, such as active proteins involved in signal transduction and
non-coding RNAs involved in transcriptional regulation, to long-term effects through target cell
reprogramming. As such, bone marrow cells that have been educated and reprogrammed by tumor-derived
EVPs can maintain their altered function upon serial transplantation (whereby donor hematopoietic stem