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Page 14 Cai et al. Extracell Vesicles Circ Nucleic Acids 2023;4:262-82 https://dx.doi.org/10.20517/evcna.2023.10

bacteria, oomycetes, and parasites. While nematodes, bacteria, and yeast have been shown to traffic
biological material into their mammalian hosts [42,141,143,144] , recent studies have shown that mammalian hosts
[122]
also use EVs to traffic sRNAs to interacting organisms .

There is clear evidence that plants use EVs to transport RNA and proteins into interacting organisms,
analogous to how mammalian cells use EVs to shuttle RNA and other biological materials between cells or
tissues within a single organism or between interacting organisms. Similarly, microbes generate EVs with a
variety of contents in order to communicate with other microbes or their hosts. The study of EVs is
expanding our understanding of organismal interactions. A new study by Hackl et al. discovered that the
marine bacterial species Prochlorococcus secretes vesicles containing strain-specific DNA transposons that
facilitate horizontal gene transfer of metabolic and bacteriophage resistance genes between Prochlorococcus
[172]
strains , demonstrating that these EVs are very stable and can survive in seawater. Recently, it was also
shown that the algal species Emiliania huxleyi, when infected with E. huxleyi virus, secretes vesicles
containing sRNAs that influence the population dynamics of interacting marine microorganisms such as
phytoplankton and bacteria . These studies demonstrate the essential role of vesicles in the assembly and
[173]
communication of marine microbial communities, highlighting the underappreciated role of EVs in inter-
organismal cellular interactions, microbial evolution, and environmental stability. More research is needed
to understand how microbes such as bacteria and fungi use EVs for adaptation and intra- and inter-species
communication.

Although five distinct classes of plant EVs have been identified, the characterization of their biological
functions, cargoes, biogenesis and biomarkers lags behind that of mammalian EVs. Furthermore, studies of
microbial EVs are even further limited. The functions of cargoes between species are often not as apparent
as those between tissues within the same organism. Thus, the cargoes and biological functions of EVs in
plants and microbes are and will continue to be an intriguing yet challenging direction in the field of vesicle
biology. The current task of the field is to identify more EV markers in plants and microbial species and to
improve methods to isolate EVs and purify specific classes of EVs.

Although EV-mediated transport is a key mechanism for RNA protection and delivery between hosts and
microbes, EV-independent RNA transport has also been reported to date. In human plasma, extracellular
RNA and protein complexes were identified, such as AGO protein-RNA complexes and high-density
lipoprotein-RNA complexes [174,175] . In plants, nearly 30% of host Arabidopsis sRNAs found in B. cinerea cells
were not found in EVs , suggesting an EV-independent pathway for transporting these sRNAs. However,
[29]
EV-independent extracellular RNAs and RNA-protein complexes would likely undergo rapid degradation
in the plant extracellular environment, which contains numerous nucleases and proteases [53,54] . It remains to
be explored how EV-independent extracellular RNAs and RNA complexes are secreted and survive in
extracellular environments, and whether these RNAs are functional and mediate cross-kingdom RNAi.
Overall, encapsulation of RNA in EVs is an effective strategy for cells to protect extracellular RNA from
degradation and may also mediate efficient RNA uptake into interacting cells and organisms.

A better understanding of plant EVs and cross-kingdom RNAi will promote the development and
application of a new generation of RNA “fungicides” to control plant diseases caused by eukaryotic
pathogens [35,163] . In addition, plant-derived EVs and nanovesicles have a potential role in novel medical
therapies [77,78] . Research has begun to develop PDNVs into therapeutic agents because of their inherent
ability to interact with human cells and influence protein and metabolite composition. However, more
research is required to fully characterize the diversity of cargoes and the overall effects of PDNVs. In the
future, plant-derived EVs could be engineered to carry specific cargoes, such as therapeutic RNAs or drugs,