Biosensors and Nanotheranostics

1. Introduction

Inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing-remitting disorder defined by sustained inflammation of the gastrointestinal tract (Chang, 2020). Once regarded as a largely Western affliction, IBD has over the past several decades spread into a worldwide health problem, and its rising incidence now imposes a considerable socioeconomic strain on health systems (Bai et al., 2024). Its origins are genuinely multifactorial: genetic susceptibility, environmental exposures, immune dysregulation, breakdown of the mucosal epithelial barrier, and dysbiosis of the gut microbiota all appear to act together rather than in isolation (Chang, 2020; Glassner et al., 2020). At the tissue level, the disease reflects a lost balance between pro-inflammatory cytokines—tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8)—and their anti-inflammatory counterparts, a skew that drives persistent ulceration, progressive mucosal injury, and, over the long term, an elevated risk of colitis-associated cancer (CAC) (Cai et al., 2022; Chang, 2020).

Current pharmacotherapy, despite real progress, still leans heavily on conventional chemical agents such as 5-aminosalicylic acid derivatives, corticosteroids, and immunosuppressants, together with biologics that target specific inflammatory mediators—most prominently anti-TNF-α monoclonal antibodies like infliximab (Yang & Merlin, 2019). These interventions help many patients, but they share a set of stubborn limitations. Orally delivered small molecules and biologics are undermined by low localized bioavailability, pre-systemic degradation in the harsh luminal environment, poor intestinal retention, and rapid clearance (Xu et al., 2025; Yang & Merlin, 2019). Prolonged systemic exposure to immunosuppressive and biologic drugs, meanwhile, is frequently accompanied by serious adverse events, opportunistic infection, and eventual loss of response or drug resistance (Pabari et al., 2019). Taken together, these shortcomings make a compelling case for targeted, biocompatible oral drug-delivery systems that can concentrate therapy at inflamed colonic sites while sparing the rest of the body (Cai et al., 2022; Xu et al., 2025).

Nanomedicine has pursued this goal with synthetic nanocarriers—liposomes, polymeric nanoparticles, and metallic nanostructures among them. Such carriers do shield their payloads from digestive enzymes, yet their clinical translation has been slowed by intrinsic drawbacks, including potential cytotoxicity, the risk of provoking inflammation, limited cellular uptake, manufacturing complexity, and cost (Filipczak et al., 2020; Paris et al., 2019). Mammalian cell-derived extracellular vesicles, such as exosomes from stem or dendritic cells, have also shown promise as natural vehicles, but their use is constrained by low isolation yields, high operating costs, the possibility of transmitting human pathogens or pro-malignant material, and demanding regulatory requirements (Dad et al., 2021; Orefice et al., 2023).

It is in this gap that plant-derived exosome-like nanovesicles (PELNs)—variously termed plant-derived nanovesicles (PDNVs), plant-derived extracellular vesicles (PDEVs), or plant exosome-like nanoparticles (PENs)—have emerged as an eco-friendly biological nanoplatform for IBD therapy (Dad et al., 2021; Kim et al., 2022). PELNs are nanoscale, lipid-bilayer-enclosed vesicles, typically 30–500 nm across, that are naturally secreted by edible fruits, vegetables, and medicinal plants including ginger, grape, grapefruit, garlic, broccoli, tea, turmeric, and Portulaca oleracea (Zhao et al., 2024). Generated through endosomal multivesicular-body (MVB) pathways, vacuolar secretion, or exocyst-positive organelles, they recapitulate much of the morphology, structure, and function of mammalian exosomes (Li et al., 2026; Song et al., 2025).

Crucially, PELNs hold several advantages over both synthetic particles and mammalian vesicles. Because they derive from dietary or medicinal botanical sources, they tend to be highly biocompatible, non-toxic, and only weakly immunogenic in human cells, and—since plants do not harbor mammalian or zoonotic pathogens—they sidestep the risk of cross-species viral contamination (Li et al., 2026; Vetsci et al., 2026). From a production standpoint, their raw material is abundant, cheap, scalable, and high-yielding (Song et al., 2025). They are also remarkably stable in the gut: a membrane rich in phosphatidic acid (PA), phosphatidylcholine (PC), and digalactosyldiacylglycerol (DGDG) lets them withstand wide pH swings (pH 2.0–8.0), gastric acid, pancreatic enzymes, and bile salts, so that vesicle integrity is largely preserved during transit through the stomach and small intestine (Zhang et al., 2026; Zhao et al., 2024).

Perhaps the defining feature of PELNs is their dual functionality—they are at once intrinsically active therapeutics and versatile delivery vectors. On one side, pristine PELNs carry an endogenous cargo of functional plant microRNAs (miRNAs), structural lipids, defense proteins, and secondary metabolites such as 6-gingerol, curcumin, raphanin, and flavonoids (Kim et al., 2022; Teng et al., 2018). Through cross-kingdom regulation, these molecules exert real biological effects: direct anti-inflammatory signaling (suppressing NF-κB, NLRP3, and MAPK), a push toward M1-to-M2 macrophage polarization, restoration of tight-junction proteins (ZO-1, Occludin, Claudin-4), activation of Lgr5+ intestinal stem-cell proliferation via Wnt/β-catenin, and structural remodeling of the microbiota (Gao et al., 2022; Ju et al., 2013; Teng et al., 2018). On the other side, the amphiphilic bilayer and net-negative zeta potential of PELNs afford passive colonic targeting through electrostatic interaction with positively charged inflammatory proteins—transferrin and eosinophil cationic protein among them—that are overexpressed at mucosal lesions (Tirosh et al., 2009; Zhang et al., 2026). The same vesicles can be loaded with exogenous payloads ranging from hydrophobic drugs (doxorubicin, methotrexate, paclitaxel) and natural compounds (curcumin, 6-shogaol) to fragile nucleic acids (siRNA-CD98, antisense oligonucleotides) and biologic antibodies (infliximab), typically via sonication, incubation, or electroporation (Mao et al., 2021; Wang et al., 2014; Zhang et al., 2017).

Even with this momentum, the field confronts clear translational hurdles: isolation protocols are not standardized, regulatory classification is ambiguous, batch-to-batch variation is common, pharmacokinetic profiling is incomplete, and clinical data remain sparse (Bai et al., 2024; Tan et al., 2026). A systematic synthesis of what is currently known about PELNs as natural oral carriers for IBD is therefore timely, both to map the mechanistic landscape and to connect basic phytotherapy with clinical nanomedicine. The present review pursues exactly that synthesis—covering the biogenesis, composition, therapeutic mechanisms, bioengineering strategies, and clinical translation of PELNs, with a particular focus on IBD.

2. Edible Plant Nanovesicles Repair the Inflamed Gut and Carry Oral Biologics in Inflammatory Bowel Disease

This section brings together the mechanistic and compositional literature on PELNs as next-generation platforms for IBD. It moves from how the vesicles are made and what they contain, through their behavior in the gut and their therapeutic mechanisms, to the engineering strategies that extend their utility and the obstacles that still limit clinical use. The physicochemical and biochemical profiles compiled across botanical sources are summarized in Table 1; the multi-targeted anti-colitic mechanisms of pristine vesicles in Table 2; the payload-loaded, bioengineered constructs in Table 3; and the comparative standing of PELNs against mammalian and synthetic carriers in Table 4.

2.1 Biogenesis, Structural Architecture, and Molecular Composition

Plant-derived exosome-like nanovesicles—whether labeled PDEVs, PDNVs, or PENs—are spherical, membrane-enclosed structures that generally fall between 30 and 500 nm in diameter (Bai et al., 2024; Li et al., 2026; Zhang et al., 2026). Secreted by edible fruits, vegetables, and traditional medicinal herbs, they share considerable structural, morphological, and functional overlap with mammalian extracellular vesicles (Dad et al., 2021; Shinge et al., 2022). Where they diverge is in origin: unlike mammalian exosomes, which depend strictly on endosomal machinery, plant cells release nanovesicles through three distinct routes—the canonical MVB pathway, the exocyst-positive-organelle (EXPO) pathway, and the vacuolar pathway (Deng et al., 2025; Song et al., 2025). The MVB route is the principal mechanism, in which inward invagination of the late endosomal membrane generates intraluminal vesicles that are later released into the apoplast as the MVB fuses with the plasma membrane (Li et al., 2026; Zuo et al., 2026). The EXPO pathway, by contrast, works independently of endosomes via double-membrane organelles that dock at the cell wall, while the vacuolar pathway involves fusion of hydrolase-rich central vacuoles with the plasma membrane during defense responses (Li et al., 2026; Zhao et al., 2024). These three converging routes, and the resulting vesicle architecture and cargo, are depicted in Figure 1.

Structurally, each PELN is a protective phospholipid bilayer wrapped around a complex lumen of nucleic acids, functional proteins, structural lipids, and secondary metabolites (Dad et al., 2021; Zhao et al., 2024). The lipidomic signature sets them apart from mammalian vesicles: where mammalian exosomes are rich in cholesterol and sphingomyelin, PELNs are enriched in phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), digalactosyldiacylglycerol (DGDG), monogalactosyldiacylglycerol (MGDG), and glycosylinositolphosphoceramides (GIPCs) (Chen et al., 2025; Feng et al., 2025; Zhao et al., 2024). Phosphatidic acid is especially consequential, since it drives membrane fusion, cellular internalization, and cross-species signaling with gut bacteria (Mammadova et al., 2023; Teng et al., 2018).

The proteomic side includes cytosolic and membrane-associated proteins such as heat-shock proteins (HSP70, HSP90), annexins, actin, and aquaporins, with candidate surface markers—PENETRATION 1 (PEN1), PEN3, and Tetraspanin-8 (TET8)—identified in particular botanical sources (Di Giulio et al., 2023; Shinge et al., 2022; Zhao et al., 2024). Importantly, PELNs package functional non-coding RNAs, predominantly microRNAs of 20–22 nucleotides and small interfering RNAs, that carry a 2′-O-methyl modification at their 3′ termini (Baldrich et al., 2019; Bartel, 2004). That single chemical detail matters a great deal, because it shields plant miRNAs from intestinal RNases and so permits stable cross-kingdom gene regulation in human recipient cells (Zhao et al., 2024). Finally, the vesicles retain the bioactive metabolites of their source plant—6-gingerol and 6-shogaol in ginger, curcumin in turmeric, raphanin in broccoli, and flavonoids in citrus (Kim et al., 2022; Lin et al., 2026; Mammadova et al., 2023). The source-by-source breakdown of size, charge, and cargo is detailed in Table 1.

2.2 Gastrointestinal Stability, Mucosal Tropism, and Comparative Advantages

A central problem in oral IBD therapy is that active compounds are rapidly degraded, chemically and enzymatically, in the upper gut (Tirosh et al., 2009; Xu et al., 2025). PELNs manage to get past these barriers largely because of their resilient bilayer (Lin et al., 2025; Zhang et al., 2026). Experimental work shows that they hold their structural integrity, size distribution, and surface charge across pH 2.0–8.0, resisting gastric acid, pepsin, trypsin, and bile salts (Lin et al., 2025; Song et al., 2025). Beyond mere survival, PELNs show a useful tropism for inflamed colonic tissue (Lin et al., 2025; Ning et al., 2025). Their nanoscale size and hydrophilic surface let them diffuse through the thickened mucus layer without becoming trapped (Lai et al., 2009), and their net-negative zeta potential (typically −10 to −30 mV) promotes accumulation at inflamed lesions through electrostatic attraction to positively charged proteins such as transferrin and eosinophil cationic protein (Tirosh et al., 2009; Zhang et al., 2026).

Set against synthetic platforms and mammalian exosomes, the comparative case for PELNs is reasonably strong (Dad et al., 2021; Li et al., 2026). Synthetic carriers can be cytotoxic, may trigger inflammation, and demand complex, costly synthesis (Filipczak et al., 2020; Paris et al., 2019). Mammalian exosomes are hampered by low yields, high cost, batch variability, and the possibility of transmitting pathogens or oncogenic material (Dad et al., 2021; Orefice et al., 2023). PELNs, being derived from edible plants, instead offer biocompatibility, low immunogenicity, scalable low-cost production, and freedom from zoonotic pathogens (Song et al., 2025; Vetsci et al., 2026). A point-by-point comparison of source, yield, stability, biosafety, intrinsic activity, and standardization is laid out in Table 4 and summarized schematically in Figure 4.

2.3 Multi-Targeted Therapeutic Mechanisms in IBD

Across the literature, the therapeutic activity of pristine PELNs converges on three recurring mechanisms—immune modulation, barrier repair, and microbiota remodeling—summarized together in Table 2 and Figure 2.

2.3.1 Anti-Inflammatory Signaling and Cytokine Suppression

The pathology of UC and CD rests on aberrant activation of innate and adaptive immune cells and the excessive cytokine output that follows (Chang, 2020; Glassner et al., 2020). Pristine PELNs intervene directly in the relevant signaling cascades (Li et al., 2026; Wu et al., 2026). Unmodified vesicles from ginger, garlic, turmeric, and ginseng inhibit the NF-κB and MAPK pathways, preventing nuclear translocation of p65 and dampening downstream inflammatory targets (Chen et al., 2019; Gao et al., 2022; Zhao et al., 2024). Specific lipids reinforce this effect: 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) in garlic-chive vesicles and phosphatidic acid in ginger vesicles block assembly of the NLRP3 inflammasome, curbing caspase-1 auto-activation and lowering IL-1β and IL-18 release (Chen et al., 2019; Deng et al., 2025; Liu et al., 2022). In parallel, PELNs suppress TNF-α, IL-1β, IL-6, and IL-8 while raising anti-inflammatory mediators such as IL-10 and heme oxygenase-1 (HO-1) in intestinal epithelial cells and macrophages, and they promote the reprogramming of pro-inflammatory M1 macrophages into tissue-protective M2 cells (Gao et al., 2022; Ka et al., 2024; Wang et al., 2014).

2.3.2 Epithelial Barrier Repair and Mucosal Regeneration

Loss of tight-junction (TJ) integrity is a hallmark of colonic damage in IBD (Suzuki, 2013; van der Post et al., 2019). Oral PELNs restore barrier function by upregulating TJ proteins (ZO-1, Occludin, Claudin-1, Claudin-4) and adherens junction proteins (E-cadherin) in colonic tissue (Choi et al., 2022; Eom et al., 2022; Li et al., 2026). They also stimulate endogenous repair: grape-derived vesicles cross the mucus layer and are taken up by Lgr5+ intestinal stem cells in colonic crypts via macropinocytosis, after which their lipid fractions activate Wnt/β-catenin signaling, driving nuclear translocation of β-catenin and Tcf4-mediated transcription of self-renewal genes (Sox2, Nanog, Oct4, c-Myc) to accelerate epithelial regeneration and wound healing (Ju et al., 2013; Zhao et al., 2024).

2.3.3 Inter-Kingdom Regulation of the Gut Microbiome

Dysbiosis—reduced diversity, depletion of short-chain-fatty-acid (SCFA) producers, and expansion of pathobionts—contributes to IBD (Guo et al., 2020; Glassner et al., 2020). PELNs act on this axis through cross-kingdom regulation (Li et al., 2026; Teng et al., 2018). Ginger-derived miRNAs such as mdo-miR7267-3p are taken up by Lactobacillus rhamnosus GG in a phosphatidic-acid-dependent manner and target the bacterial monooxygenase gene ycnE, prompting secretion of indole-3-carboxaldehyde (I3A); I3A then activates the aryl hydrocarbon receptor (AHR) pathway in host immune cells, stimulating IL-22 to reinforce barrier defense (Teng et al., 2018; Zuo et al., 2025). Garlic-derived vesicles enriched in peu-MIR2916-p3 and Han-miR3630-5p selectively expand beneficial Bacteroides thetaiotaomicron and Lachnospiraceae while suppressing Proteobacteria, Escherichia-Shigella, and Helicobacter, and this remodeling raises colonic SCFAs (acetate, propionate, butyrate) to build an anti-colitic microenvironment (Wang et al., 2024; Wang et al., 2025; Zhu et al., 2023).

2.4 Bioengineering, Drug Encapsulation, and Targeted Delivery

Although unmodified PELNs are already bioactive, their loading capacity can be engineered to carry exogenous payloads, combining native efficacy with localized delivery (Li et al., 2024; Ning et al., 2025). Encapsulation strategies include passive co-incubation, probe sonication, electroporation, freeze–thaw cycling, and membrane extrusion (Langellotto et al., 2025; Shinge et al., 2022). Probe sonication, for instance, transiently disrupts the bilayer to admit hydrophilic and hydrophobic drugs, after which the membrane self-seals without disturbing vesicle morphology (Villata et al., 2020). Reported payloads span small-molecule anti-inflammatories and chemotherapeutics (curcumin, methotrexate, 5-aminosalicylic acid, doxorubicin) and fragile nucleic acids (siRNA-CD98, TNF-α siRNA) (Mao et al., 2021; Wang et al., 2014; Zhang et al., 2017). A striking example is ginger nanolipids loaded with siRNA against CD98, which lowered intestinal CD98 expression and colonic inflammation while reducing the effective siRNA dose by roughly 10,000-fold relative to free siRNA (Zhang et al., 2017; Zhao et al., 2024). These payload-loaded constructs are catalogued in Table 3 and the overall loading-and-delivery scheme is shown in Figure 3.

A particularly notable advance is the oral delivery of monoclonal antibodies within PELN platforms (Mao et al., 2021). Infliximab, an anti-TNF-α antibody, is normally given by intravenous infusion, which carries risks of systemic immunosuppression, opportunistic infection, and loss of response (Pabari et al., 2019; Yusuf, 2026). Yusuf (2026) developed infliximab-loaded plant nanoparticles (I-PENs) using ginger-derived nanoparticles (I-GDNPs) and newly isolated Cynara edulis (Chunga) nanoparticles (I-ChNPs); formulated by electrostatic adsorption, these achieved loading efficiencies of about 13% for GDNPs and 23–29% for ChNPs. In an inflamed Caco-2/THP-1 co-culture model, I-PEN constructs showed superior transepithelial transport and basolateral delivery of intact infliximab relative to free antibody, reaching lamina propria macrophages, reducing IL-6 and IL-8 secretion, and restoring transepithelial electrical resistance (TEER) more effectively than free infliximab—with native vesicle metabolites apparently acting in synergy with the loaded antibody (Mao et al., 2021; Yusuf, 2026).

2.5 Translational Bottlenecks, Quality Control, and Clinical Outlook

For all the preclinical promise, several technical and regulatory issues stand between PELNs and the clinic (Bai et al., 2024; Song et al., 2025; Tan et al., 2026). The first is isolation. Differential ultracentrifugation remains the workhorse but is labor-intensive, slow, prone to inducing aggregation, and hard to scale, which has pushed the field toward tangential-flow filtration (TFF), size-exclusion chromatography (SEC), and electrophoresis-with-dialysis (ELD) as more scalable alternatives (Huang et al., 2021; Li et al., 2026; Zuo et al., 2026). The second is standardization. Because PELNs come from agricultural material, their composition—miRNA levels, lipid ratios, metabolite content—varies with strain, geography, soil, climate, and harvest season, and the absence of universal protein markers comparable to mammalian tetraspanins (CD63, CD9, CD81) complicates validation under Good Manufacturing Practice (GMP) frameworks (Dad et al., 2021; Rodríguez de Lope et al., 2025; Tan et al., 2026). The comparative standardization gap relative to mammalian and synthetic carriers is captured in Table 4, and the full translational roadmap is summarized in Figure 4.

Early clinical evaluation has nonetheless begun. A Phase I trial (NCT04879810) of oral ginger-derived exosomes in IBD patients reported favorable safety, tolerability, and no systemic toxicity (Zhang et al., 2026), and a pilot study of oral Atractylodes macrocephala-derived nanovesicles (AMEVLPs) in active UC reduced rectal mucosal erosion and purulent exudate (Tan et al., 2025). Translating these early signals into approved therapies will depend on interdisciplinary work spanning standardized manufacturing, pharmacokinetic characterization, and multicenter clinical trials (Li et al., 2026; Song et al., 2025; Zuo et al., 2026).

3. Methods

This review was conducted as a structured narrative synthesis of the preclinical and early-clinical literature on plant-derived exosome-like nanovesicles as oral drug carriers for inflammatory bowel disease. The methodology below is reported in sufficient detail to allow the search and selection process to be reproduced by other investigators, following the general principles used for literature identification, screening, and data extraction in biomedical reviews.

3.1 Information Sources and Search Strategy

Peer-reviewed literature was identified by searching the biomedical and scientific databases PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, supplemented by the ClinicalTrials.gov registry for interventional study records. The search combined controlled vocabulary and free-text terms across three concept blocks joined with the Boolean operator AND, with synonyms within each block joined by OR. Block 1 (vesicle): "plant-derived exosome-like nanovesicles" OR "plant-derived extracellular vesicles" OR "plant exosome-like nanoparticles" OR "plant-derived nanovesicles" OR "PELN" OR "PDEV" OR "PDNV". Block 2 (indication): "inflammatory bowel disease" OR "ulcerative colitis" OR "Crohn's disease" OR "colitis" OR "colitis-associated cancer". Block 3 (function): "drug delivery" OR "oral delivery" OR "anti-inflammatory" OR "gut microbiota" OR "intestinal barrier" OR "microRNA". Source-specific terms (for example, ginger, grape, grapefruit, garlic, broccoli, turmeric, Cynara edulis) and payload terms (for example, infliximab, siRNA, curcumin, methotrexate) were added iteratively to capture mechanism- and formulation-specific reports.

3.2 Eligibility Criteria

Studies were eligible if they (i) characterized the biogenesis, composition, physicochemical properties, or isolation of PELNs; (ii) evaluated pristine or bioengineered PELNs in in vitro, in vivo, or clinical models relevant to IBD; or (iii) compared PELNs with mammalian extracellular vesicles or synthetic nanocarriers. Primary research articles, authoritative reviews, a doctoral dissertation reporting original experimental data, and registered clinical trials were considered. Records were excluded if they fell outside the scope of gastrointestinal or inflammatory applications, lacked extractable methodological or mechanistic detail, or were not available in English. No restriction was placed on publication year, reflecting the rapid and recent expansion of the field.

3.3 Study Selection and Data Extraction

Records retrieved from all sources were de-duplicated and screened first by title and abstract and then by full text against the eligibility criteria. For each included study, the following data were extracted into a structured matrix: botanical source and species; isolation and purification protocol; particle size and zeta potential; endogenous molecular cargo (lipids, proteins, miRNAs, and secondary metabolites); experimental model (in vitro cell line, in vivo colitis model, or clinical setting); molecular targets and signaling pathways; encapsulated payload and loading method where applicable; and the principal biological or therapeutic outcomes. Reported DOIs and registry identifiers were retained verbatim from the source records.

3.4 Data Synthesis and Presentation

Because the included studies were methodologically heterogeneous—differing in botanical source, isolation technique, model system, and outcome measure—a quantitative meta-analysis was not appropriate. Findings were therefore synthesized narratively and organized thematically around four axes: (i) physicochemical and biochemical characterization across botanical sources; (ii) multi-targeted anti-colitic mechanisms of pristine vesicles; (iii) bioengineered, payload-loaded constructs; and (iv) comparative advantages and translational readiness. The extracted evidence was consolidated into four summary tables (Table 1, Table 2, Table 3, and Table 4) and four schematic figures (Figure 1, Figure 2, Figure 3, and Figure 4), which together provide the structured, reproducible basis for the synthesis presented in the following sections.

4. Preclinical Efficacy, Biological Signatures, and Bioengineering Outcomes of PELNs in IBD

4.1 Physicochemical Diversity, Structural Integrity, and Yield Across Botanical Sources

When the extraction data are laid side by side, a fairly consistent picture emerges. PELNs isolated from very different dietary and medicinal plants tend to converge on nanoscale dimensions—mostly 30 to 500 nm in hydrodynamic diameter—and on negative surface charges in the range of roughly −10 to −50 mV (Table 1). Transmission electron microscopy, in study after study, shows the same saucer- or cup-shaped bilayer morphology that is familiar from mammalian vesicles (Dad et al., 2021). That said, the isolation method clearly leaves its mark: differential ultracentrifugation paired with density-gradient centrifugation or size-exclusion chromatography remains the benchmark for stripping out soluble protein contaminants while keeping the membrane intact (Huang et al., 2021; Li et al., 2026).

Source-specific numbers fill in the detail (Table 1; Figure 1). Ginger-derived nanoparticles from fresh Zingiber officinale rhizomes run to average diameters of about 230–280 nm with zeta potentials of −12.1 to −18.4 mV (Zhang et al., 2016a). Cynara edulis (Chunga) nanovesicles, isolated by a top-down differential-centrifugation protocol, come in at roughly 226–290 nm (Yusuf, 2026). Broccoli vesicles are markedly smaller (18.3–118.2 nm, mean near 32 nm), grapefruit vesicles span a broader 50–800 nm, and garlic vesicles sit between 70 and 200 nm (Deng et al., 2017; Wang et al., 2014; Zhu et al., 2023). The spread is a reminder that "PELN" is really a family of particles rather than a single entity.

Lipidomic profiling reinforces the point made earlier about composition (Table 1). Rather than the cholesterol and sphingomyelin that dominate mammalian vesicles, PELNs carry high proportions of bioactive phospholipids and galactolipids—phosphatidic acid making up as much as 41.9% of total lipids in ginger nanoparticles, alongside PC, PE, DGDG, and MGDG (Chen et al., 2025; Zhao et al., 2024). Mass spectrometry confirms that the vesicles also carry their parent plant's secondary metabolites—6-gingerol and 6-shogaol in ginger, sulforaphane in broccoli, curcumin in turmeric, naringin in grapefruit, and hydroxymethylfurfural and trans-cinnamic acid in Chunga (Kim et al., 2022; Yusuf, 2026). Small-RNA sequencing, finally, recovers rich pools of miRNAs protected by 3′-terminal 2′-O-methylation, which is what allows them to persist in gastrointestinal fluids and act across kingdoms (Baldrich et al., 2019; Zhao et al., 2024).

4.2 In Vitro and In Vivo Anti-Inflammatory Signaling

Across dextran-sulfate-sodium (DSS)-induced colitis models, oral administration of unmodified PELNs produces a broadly reproducible therapeutic response: lower disease-activity-index (DAI) scores, blunted weight loss, preserved colon length, and reduced splenomegaly, with histology confirming less mucosal erosion, ulceration, and inflammatory infiltration (Table 2) (Gao et al., 2022; Zhu et al., 2023). At the cellular level, fluorescently labeled vesicles are rapidly taken up by intestinal epithelial cells (Caco-2) and by F4/80+ lamina propria macrophages (Wang et al., 2014).

The mechanistic readouts, summarized in Table 2 and Figure 2, cluster into three recurring effects. First, vesicles from ginger, turmeric, garlic, and ginseng inhibit LPS-induced NF-κB p65 phosphorylation and nuclear translocation, which downregulates TNF-α, IL-1β, IL-6, and IL-8 (Chen et al., 2019; Gao et al., 2022). Second, lipid constituents—DLPC in garlic-chive vesicles and PA in ginger vesicles—block NLRP3 inflammasome assembly, preventing caspase-1 auto-cleavage and limiting mature IL-1β and IL-18 release together with pyroptotic cell death (Chen et al., 2019; Liu et al., 2022). Third, treatment lowers iNOS and COX-2 while pushing M1 macrophages toward an M2 phenotype, raising IL-10 and HO-1 through the Nrf2/Keap1 pathway (Gao et al., 2022; Ka et al., 2024). It is worth noting that these three effects are not cleanly separable; in most reports they appear together, which is part of what makes the vesicles attractive.

4.3 Epithelial Barrier Restitution and Stem-Cell Regeneration

Barrier failure is both cause and consequence of colonic injury, so the barrier data are worth dwelling on (Table 2; Figure 2). Oral PELNs restore TEER across Caco-2 monolayers and reduce leakage of diamine oxidase and FITC-dextran, with Western blotting and RT-qPCR confirming upregulation of ZO-1, Occludin, Claudin-1, and Claudin-4, along with E-cadherin and Mucin-2 (Choi et al., 2022; Eom et al., 2022). Beyond simply sealing the barrier, grape-derived vesicles reach Lgr5+ intestinal stem cells in colonic crypts via macropinocytosis and activate canonical Wnt/β-catenin signaling, triggering β-catenin nuclear translocation and Tcf4-mediated transcription of Sox2, Oct4, Klf4, EGFR, and c-Myc—so that crypt regeneration and wound healing follow (Ju et al., 2013; Zhao et al., 2024). This regenerative cascade is depicted in Figure 2.

4.4 Inter-Kingdom Microbiota Remodeling and SCFA Synthesis

16S rRNA sequencing shows, fairly consistently, that oral PELNs reverse colonic dysbiosis in colitic mice and restore microbial diversity (Table 2) (Li et al., 2026; Teng et al., 2018). In DSS models they depress pathobionts (Proteobacteria, Escherichia-Shigella, Helicobacter) while expanding Bacteroides thetaiotaomicron, Lactobacillus rhamnosus, Akkermansia muciniphila, and Lachnospiraceae (Wang et al., 2024; Zhu et al., 2023). The mechanism, where it has been worked out, runs through targeted miRNA delivery: ginger mdo-miR7267-3p is absorbed by L. rhamnosus GG in a PA-dependent manner and silences the bacterial ycnE gene, stimulating production of indole-3-carboxaldehyde, an AHR ligand that induces IL-22 and so reinforces barrier defense (Teng et al., 2018; Zuo et al., 2025). Restoring these commensal communities raises colonic SCFAs—acetate, propionate, and butyrate—which feed colonocytes and help hold immune homeostasis in place (Wang et al., 2025). This host–microbial axis is summarized schematically in Figure 2.

4.5 Delivery Performance of Payload-Loaded Bioengineered PELNs

Engineered PELNs perform well across several payload classes, as compiled in Table 3 and illustrated in Figure 3. For small molecules, loading curcumin into ginger vesicles or methotrexate into grapefruit vesicles (GMTX) improves solubility and stability in intestinal fluids; GMTX in particular homes to colonic macrophages through surface PA interactions and suppresses DSS colitis while avoiding the systemic toxicity of free methotrexate (Huang et al., 2024; Wang et al., 2014). For nucleic acids, ginger nanolipids carrying siRNA-CD98 silence the target in colonic tissue at roughly a 10,000-fold lower effective dose than free siRNA, attenuating colitis and limiting progression to CAC, while ginger vesicles coated with a ZIF-8 framework protect anti-TNF-α siRNA against gastric acid (pH 2.0) to enable targeted colonic release (Mao et al., 2021; Zhang et al., 2017).

The antibody data are perhaps the most clinically suggestive (Table 3; Figure 3). In a 3D co-culture of inflamed Caco-2 monolayers and THP-1 macrophages, infliximab-loaded plant nanoparticles based on ginger (GDNPs) and Chunga (ChNPs) reached loading efficiencies of 13% and 23–29% respectively by electrostatic adsorption (Yusuf, 2026). The constructs underwent transcytosis across the epithelial monolayer, delivered functional infliximab to sub-epithelial macrophages, restored Caco-2 TEER to more than 70% (versus roughly 65% for free infliximab and 26–43% for unloaded vesicles), and cut basolateral IL-6 and IL-8 more effectively than free antibody (Yusuf, 2026). One hesitates to over-read a single co-culture study, but the direction of the effect is consistent and the magnitude is not trivial.

4.6 Comparative Efficacy, Gastrointestinal Stability, and Biosafety

Finally, the comparative and safety data (Table 4; Figure 4) help explain the enthusiasm. Because their membranes are rich in PA, PC, DGDG, and phytosterols, PELNs hold size and cargo integrity across pH 2.0–8.0 and resist gastric acid, pepsin, trypsin, and bile salts (Zhang et al., 2026; Zhao et al., 2024). Toxicological assessment in animals has so far found no systemic organ toxicity, no notable blood-chemistry changes, and no mortality after oral dosing; compared with mammalian exosomes, PELNs show something on the order of 60–80% lower immunogenicity and are free of zoonotic pathogens and oncogenic risk (Li et al., 2026; Vetsci et al., 2026). Intravenous safety studies in pregnant rodents add a further, somewhat unexpected point in their favor—the vesicles do not appear to cross the placental barrier (Song et al., 2025). These are early findings rather than settled conclusions, but as a safety profile it is a promising place to start.

5. Interpreting the Evidence and Charting the Path to Clinical Translation

5.1 A Convergent, Multi-Targeted Mode of Action

What stands out most, reading across these studies, is how often independent groups—working with different plants, different models, and different readouts—arrive at the same three-part mechanism: calm the inflammatory signaling, rebuild the barrier, and reset the microbiota (Table 2; Figure 2) (Gao et al., 2022; Ju et al., 2013; Teng et al., 2018). That convergence is reassuring, because IBD is not a single-pathway disease, and agents that hit only one node tend to disappoint. The dual identity of PELNs—therapeutic cargo and delivery vehicle in one particle—means that a loaded construct can, at least in principle, act on several fronts at once (Li et al., 2026; Yusuf, 2026). Whether that theoretical advantage survives contact with the complexity of human disease is, of course, the open question.

5.2 Bioengineering Extends but Does Not Replace Native Activity

The engineering literature (Table 3; Figure 3) suggests a useful framing: loading does not so much replace the vesicle's intrinsic activity as build on top of it. The siRNA-CD98 result, with its roughly 10,000-fold dose reduction, is the clearest illustration that the carrier is doing real work rather than merely coming along for the ride (Zhang et al., 2017). The infliximab studies push the idea further, into oral biologic delivery that would have seemed implausible a decade ago, and the apparent synergy between native metabolites and the loaded antibody is intriguing—though, again, it rests so far on in vitro co-culture rather than in vivo efficacy (Mao et al., 2021; Yusuf, 2026). It would be premature to treat a 13–29% loading efficiency as production-ready, and the field would benefit from honest reporting of the constructs that did not work as well.

5.3 Why PELNs May Outperform Existing Carriers—and Where the Case Is Thin

The comparative advantages summarized in Table 4 and Figure 4 are genuine: edible sourcing, scalability, gastrointestinal stability, low immunogenicity, and freedom from zoonotic pathogens together make a strong value proposition relative to both mammalian exosomes and synthetic particles (Dad et al., 2021; Song et al., 2025; Vetsci et al., 2026). Yet it is worth being candid about what is still soft. Much of the immunogenicity and biosafety data comes from short-term animal work, the placental-barrier finding needs independent replication, and the "60–80% lower immunogenicity" figure, while cited, derives from a limited set of comparisons (Li et al., 2026; Vetsci et al., 2026). A fair reading is that PELNs look safer and more practical than the alternatives, but that the quantitative claims should be held loosely until larger, standardized studies arrive.

5.4 Translational Bottlenecks and Quality Control

The hardest problems are, in a sense, not biological at all (Table 4; Figure 4). Isolation remains the first chokepoint: ultracentrifugation does not scale gracefully, and although TFF, SEC, and ELD are promising, none has yet become a community standard (Huang et al., 2021; Zuo et al., 2026). Standardization is the deeper issue. A product drawn from agricultural biomass will vary with strain, soil, climate, and season, and without universal markers analogous to the mammalian tetraspanins, batch validation under GMP is genuinely difficult (Rodríguez de Lope et al., 2025; Tan et al., 2026). These are solvable problems, but they are the kind that take coordinated, unglamorous effort—reference materials, agreed potency assays, MISEV-aligned reporting—rather than a single clever experiment.

5.5 Clinical Outlook and Future Directions

The clinical signals so far are modest but encouraging. The Phase I ginger-exosome trial (NCT04879810) established basic safety and tolerability, and the AMEVLP pilot in active UC showed a plausible mucosal benefit (Tan et al., 2025). Neither is powered to prove efficacy, and it would be a mistake to read more into them than they can bear. The sensible next steps are fairly clear: standardized, GMP-grade manufacturing; proper pharmacokinetic and biodistribution profiling; long-term safety evaluation; and multicenter, adequately powered trials (Li et al., 2026; Song et al., 2025; Zuo et al., 2026). If those pieces come together, the dual-acting, orally stable, low-cost profile of PELNs could make them a distinctive addition to the IBD armamentarium. If they do not, the field risks accumulating yet more elegant preclinical papers without a therapy to show for it.

6. Conclusion

Plant-derived exosome-like nanovesicles occupy an unusual and promising niche in IBD therapeutics: they are simultaneously intrinsic anti-inflammatory agents and robust oral delivery vehicles. The evidence reviewed here shows a convergent, multi-targeted mode of action—suppression of NF-κB, NLRP3, and MAPK signaling; Wnt/β-catenin-driven barrier repair; and cross-kingdom microbiota remodeling—together with gastrointestinal stability and a favorable early safety profile (Gao et al., 2022; Ju et al., 2013; Teng et al., 2018). Bioengineering has extended this native activity to small molecules, siRNA, and even oral infliximab, often with striking gains in potency and targeting (Yusuf, 2026; Zhang et al., 2017). What now limits progress is largely practical: non-standardized isolation, batch variability, incomplete pharmacokinetics, and an unsettled regulatory path (Song et al., 2025; Tan et al., 2026). Resolving these through standardized, GMP-aligned manufacturing and rigorous clinical trials will determine whether PELNs mature into genuine oral nanotherapeutics for inflammatory bowel disease.

References