Exosome-like Nanoparticles Extracted from Plant Cells for Diabetes Therapy

Abstract

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia and associated complications such as cardiovascular disease, nephropathy, retinopathy, neuropathy, and chronic non-healing wounds. Current antidiabetic therapies offer only partial glycemic control and are limited by poor bioavailability, adverse effects, and an inability to prevent disease progression. Plant-derived exosome-like nanoparticles (PENPs) have emerged as a promising class of natural nanocarriers with excellent biocompatibility, low immunogenicity, and intrinsic multi-component bioactivity. However, few reviews have addressed recent progress in PENPs for DM therapy. To capture the recent developments in this area, this review provides a systematic synthesis of recent advances in PENPs for DM therapy, covering plant sources, extraction and purification methods, molecular compositions, and therapeutic mechanisms. Preclinical studies have demonstrated that PENPs can improve hyperglycemia, enhance insulin sensitivity, regulate hepatic lipid metabolism, and promote wound healing by modulating oxidative stress, inflammation, gut microbiota, glucose metabolism, and insulin signaling. Additionally, PENPs have been shown to promote angiogenesis via glycolytic reprogramming. Despite these promising findings, challenges including scalable isolation, standardized physicochemical characterization, and clinical translation remain. Future directions include engineering multifunctional PENPs, establishing Good Manufacturing Practice (GMP)-compliant production, and conducting clinical trials to facilitate their integration into precision therapeutics for diabetes management.

Keywords: diabetes and its complications; nanobiomedicine; natural nanocarriers; plant-derived exosome-like nanoparticles; precision therapy.

Figure 1

Therapeutic roles and bioactive components of PENPs. PENPs are natural nanocarriers composed of a lipid bilayer containing lipids, proteins, and cholesterol and enriched with internal cargos such as mRNA, microRNA, DNA, proteins, and enzymes. They exert multiple therapeutic effects by enhancing insulin sensitivity, regulating glucose and lipid metabolism, modulating gut microbiota and intestinal homeostasis, promoting tissue repair, and reducing inflammation and oxidative stress. PENPs also contribute to neuroprotection and antifibrotic and antitumor activities and support targeted delivery of therapeutic agents.

Figure 2

Schematic model of EXPO-mediated unconventional secretion. EXPOs fuse with the plasma membrane and release single-membrane vesicles into the apoplast, where they rupture and deliver cytosolic proteins such as SAMS2 to the cell wall region [58]. Solid arrows indicate the progression of EXPO vesicles from formation in the cytoplasm to transport toward the plasma membrane, while the dashed arrow denotes the membrane fusion and burst step enabling extracellular release.

Figure 3

Schematic representation of the cross-kingdom regulatory mechanism by which ginger-derived PENPs deliver miRNAs to gut microbes. In addition to mdo-miR7267-3p-mediated targeting of ycnE in Lactobacillus, other miRNAs such as ath-miR167a inhibit microbial adhesion via spaC, collectively enhancing microbial metabolic output, activating AhR signaling, and promoting IL-22 dependent intestinal protection [39].

Figure 4

Schematic model of receptor-mediated endocytosis of garlic-derived PENPs via CD98 recognition. (A) Garlic-derived PENPs with intact surface proteins are labeled with coumarin-6 to enable visualization of cellular uptake. (B) Surface-expressed type II lectins on PENPs specifically recognize CD98 glycoproteins on HepG2 cell membranes, facilitating receptor-dependent endocytosis. (C) Removal of surface lectins by trypsin digestion disrupts CD98 recognition, leading to markedly reduced cellular internalization [61].

Figure 5

Grapefruit-derived extracellular-vesicle-based hybrid nanoparticles (EV-DNs) for glioma therapy. (a) The system combines the BBB-penetrating capacity of EVs with the drug-loading and targeting properties of pH-sensitive DNs; (b) The hybrid system enables efficient brain delivery and tumor-specific DOX release via αvβ3 integrin-mediated transcytosis and membrane fusion [126].

Figure 6

Proposed molecular mechanisms of mung-bean-sprout-derived PENPs in ameliorating diabetic hepatic injury. Mung-bean-sprout-derived PENPs improve diabetic conditions in HFD/STZ mice by modulating the PI3K/Akt/GLUT4/GSK-3β pathway, promoting glucose uptake and glycogen synthesis, and activating Nrf2-mediated antioxidant responses to alleviate oxidative stress-induced hepatocellular injury [131].

Figure 7

GDNPs activate Foxa2 signaling and improve metabolic health in HFD-fed mice. (A) Schematic representation of the proposed mechanism by which GDNPs modulate Foxa2 signaling in HFD-fed mice. (B) GDNPs treatment upregulates total Foxa2 expression in both cultured cells and small intestinal tissues. (C) GDNPs inhibit Foxa2 phosphorylation and reduce phosphorylated Foxa2 (pFoxa2) levels in cell culture and small intestinal tissues of lean and HFD mice. (D) GDNPs alleviate HFD-induced small intestinal damage, reduce liver weight and fat accumulation, and protect against glucose intolerance and insulin resistance [65]. * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 8

GExos promote angiogenesis and wound healing via glycolytic reprogramming. (A) Schematic illustration of GExos promoting angiogenic activity in endothelial cells under high-glucose conditions via glycolytic reprogramming, alongside the isolation and TEM characterization of GExos derived from ginseng. (B) GExos enhance endothelial cell migration and tubule formation in high-glucose culture and modulate intracellular ROS levels and oxidative phosphorylation activity. (C) Western blot and metabolic analyses demonstrating the therapeutic mechanism of GExos in promoting glycolysis-dependent angiogenesis in diabetic conditions. (D) GExos facilitate microvascular network formation and accelerate wound healing in a diabetic mouse model [143]. * p < 0.05, ** p < 0.01, **** p < 0.0001.

Figure 9

Overview of the isolation, characterization, and gut–liver regulatory effects of TNVs. TNVs were extracted via differential centrifugation and found to contain lipids, phenols, flavones, and proteins. Upon oral administration, TNVs modulated gut microbiota and promoted SCFA production, which in turn influenced bile acid metabolism and FXR-FGF19 signaling in the liver, contributing to metabolic improvement. Adapted from ref [41], 2024, under CC BY-NC 3.0 license.

Figure 10

Illustration of construction and therapeutic mechanism of a biomimetic-acid-responsive nano hydrogen producer (HMS/A@GE). (A) Schematic of the synthesis procedure of HMS/A@GE. (B) Schematic depicting that HMS/A@GE modulates the gut microbiota composition and metabolites and exerts antioxidant and anti-inflammatory effects for collaboratively improving intestinal-barrier function, glucose dysmetabolism, and liver steatosis [132].

Figure 11

GelMA/DAS/Exo hydrogel was used as a dressing for diabetic wound healing. (A) Preparation of the lemon exosome hydrogel. (B) The lemon exosome hydrogel promoted diabetic wound healing by regulating macrophage polarization (M0, M1, and M2 defined as unpolarized, pro-inflammatory, and anti-inflammatory macrophages) and promoting fibroblast and vascular endothelial cell proliferation [134].