Plant-derived extracellular vesicles as natural nucleic acid carriers in gut-liver communication: implications for metabolic liver disease

Abstract

Plant-derived extracellular vesicles (PDEVs) are nano-sized vesicles released by plant cells that contain endogenous nucleic acids, including microRNAs (miRNAs), small interfering RNAs (siRNAs), transfer RNA fragments (tRFs), and mitochondrial DNA (mtDNA). These characteristics have led to growing interest in PDEVs as naturally occurring nanocarriers suitable for oral delivery. Three biogenesis routes have been described for PDEV formation, namely multivesicular body release, plasma membrane budding, and plasmodesmatal transit. However, whether PDEVs-associated nucleic acids withstand gastrointestinal digestion and subsequently regulate mammalian gene expression remains controversial. Such interactions are generally considered within the framework of cross-kingdom gene regulation. This review summarizes current evidence concerning the nucleic acid biology of PDEVs, including their biogenesis, cargo diversity, and isolation methods. Evidence concerning gastrointestinal stability, intestinal uptake, and movement toward the liver is subsequently evaluated, along with experimental support for cross-kingdom transfer and the methodological limitations that complicate its interpretation. PDEVs-associated nucleic acids have been proposed as candidate mediators of gut-liver axis signaling in inflammatory and metabolic contexts, but their causal contribution and intravesicular localization remain incompletely defined. This review also discusses engineering strategies and potential biomarker applications. PDEVs-mediated nucleic acid transfer shows promise but requires more rigorous methodological standards. Standardized isolation workflows, stringent contamination controls, and causal validation are needed to establish biological relevance and support clinical translation.