Dietary-Derived Exosome-like Nanoparticles as Bacterial Modulators: Beyond MicroRNAs

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TL;DR

This review examines how dietary-derived exosome-like nanoparticles (DELNs) from plant and animal foods can modulate gut bacteria, acting as a third actor in host-microbe communication. Evidence shows DELNs from ginger, lemon, coconut, milk, and honey can either promote beneficial bacteria growth or inhibit pathogens, with effects mediated not only by miRNAs but also by membrane lipids and other bioactive cargo. The findings suggest DELNs represent a promising natural strategy for gut microbiota modulation and antimicrobial applications, though further mechanistic studies are needed before clinical translation.

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**Background:** Diet is a major environmental driver of gut microbiota composition, yet the mechanisms by which food compounds influence intestinal bacteria remain incompletely understood. While attention has traditionally focused on nutrients like lipids, proteins, vitamins, and polyphenols, dietary-derived exosome-like nanoparticles (DELNs) have emerged as potential mediators of transkingdom communication. These nanosized vesicles, isolated from both plant and animal food sources, carry bioactive molecules including proteins, miRNAs, lipids, and small metabolites that may interact directly with bacteria. This review compiles current knowledge on the antimicrobial capacity of DELNs and their possible molecular mechanisms, addressing a gap in the literature where most attention has previously centered on miRNA cargo rather than other bioactive components.

**Methods:** The authors conducted a narrative review of the scientific literature on DELNs isolated from edible plants (ginger, lemon, coconut, tartary buckwheat) and animal-derived foods (milk, honey). They summarized studies examining the effects of these nanoparticles on bacterial growth, gut microbiota composition, and the molecular mechanisms underlying these interactions, including lipid-mediated uptake, miRNA targeting of bacterial genes, and cargo-mediated signaling.

**Key Results:** Ginger exosome-like nanoparticles (GELNs) increased Lactobacillaceae and Bacteroidales S24-7 while inhibiting Ruminococcaceae and Clostridiaceae in C57BL/6 mice. Phosphatidic acid (PA) lipids in GELN membranes mediated preferential uptake by Lactobacillus rhamnosus GG and interacted with hemin-binding protein 35 on Porphyromonas gingivalis, leading to growth inhibition. GELN-RNAs, including miR167a, downregulated the LGG pilus protein SpaC. Lemon exosome-like nanoparticles (LELNs) increased bile resistance of LGG and inhibited Clostridioides difficile infection through a mechanism involving pectin content and the production of AhR ligands (indole-3-lactic acid and indole-3-carboxaldehyde) and lactic acid. Coconut exosome-like nanoparticles (CELNs) increased growth of Escherichia coli K-12 MG1655 and accelerated growth of Lactobacillus plantarum WCFS1, with CELNs repressing rpoC and yegH expression while elevating ccpA in MG1655. Tartary buckwheat-derived nanovesicles (TBDNs) promoted growth of E. coli and L. rhamnosus and changed human fecal microecological diversity. Bovine milk-derived EVs (MDEVs) altered murine cecal microbiota, increasing Lachnospiraceae, Firmicutes, Tenericutes, and Verrucomicrobiaceae, with effects associated with sex and age. In DSS-induced colitis mice, MDEVs partially recovered disturbed gut microbiota and significantly increased Akkermansia abundance. Honey-derived EVs (HDEVs) demonstrated bacteriostatic, bactericidal, and biofilm-inhibiting effects on Staphylococcus aureus, with antibacterial molecules MRJP1, defensin-1, and jellein-3 identified as intravesicular cargo. HDEVs showed pronounced activity against Streptococcus mutans compared to Streptococcus sanguinis. Royal jelly-derived EVs confirmed bactericidal effects on S. aureus in vivo, with no bacteria detected after 48 h in mice treated with collagen gel containing these EVs.

**Clinical Implications:** DELNs represent a promising natural alternative to synthetic antimicrobial agents and chemical preservatives in the food industry, potentially reducing undesirable side effects and changes in organoleptic properties. The ability of DELNs to selectively promote beneficial bacteria while inhibiting pathogens offers potential therapeutic applications for conditions associated with gut dysbiosis, including metabolic, immunological, and neurological disorders. The resistance of DELNs to harsh gastrointestinal conditions makes them particularly suitable for oral administration and gut-targeted interventions. However, the molecular mechanisms underlying DELN-bacteria interactions remain incompletely understood, and most evidence comes from preclinical studies. Further investigation is needed to characterize the full cargo composition of DELNs, elucidate the specific roles of non-miRNA bioactive molecules, and establish the safety and efficacy of DELN-based therapies before clinical translation can proceed.