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Prunus mume derived extracellular vesicle-like particles alleviate experimental colitis via disrupting NEK7-NLRP3
Qi Lv1, Hongqiong Yang2, Ying Xie2
1Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. qilv@njucm.edu.cn.
Abstract:
Edible plant derived extracellular vesicle-like particles (EVLPs) have garnered attention as potential therapeutic agents for chronic inflammatory diseases. Prunus mume (PM) is a functional fruit known for its gastrointestinal benefits, yet the detail material basis and potential mechanism remain unclear. Here, we reported that oral administration of prunus mume derived EVLPs (PM-EVLPs) substantially mitigated experimental colitis in mice. The in vivo bio-distribution analysis revealed that PM-EVLPs specifically targeted inflamed colon of colitis mice. Further in vitro studies demonstrated that PM-EVLPs were predominantly internalized by macrophages. The combined treatment with clodronate liposomes confirmed that macrophage was the target cell for PM-EVLPs-mediated anti-colitis activity. Mechanistically, PM-EVLPs selectively inhibited caspase-1 auto-cleavage and IL-1β secretion caused by NLRP3 inflammasome activation, while exerting minimal impact on AIM2, NLRP1 or NLRC4 inflammasome activation. Excluding the effects on mitochondrial ROS generation, K+ efflux or Ca2+ influx, PM-EVLPs disrupted the NEK7-NLRP3 interaction, thereby preventing NLRP3 inflammasome assembly. Notably, the inhibitory activity was attributed to RNAs rather than lipids or proteins within PM-EVLPs. Deep RNA sequencing, coupled with the application of miRNA mimics/inhibitors identified miR159 as the material basis for PM-EVLPs' inhibition of NLRP3 inflammasome activation and anti-colitis efficacy. Collectively, these findings suggest that PM-EVLPs represent a promising nanomedicine with potential as a novel therapeutic strategy for colitis and deserves further investigation and development.
Insights
Prunus mume derived extracellular vesicle-like particles (PM-EVLPs) effectively treat colitis in mice by targeting macrophages. These plant-derived nanoparticles inhibit NLRP3 inflammasome activation via miR159, offering a promising nanomedicine for inflammatory diseases.
Area of Science:
- Plant-derived nanoparticles
- Nanomedicine
- Immunology
Background:
- Extracellular vesicle-like particles (EVLPs) from edible plants show therapeutic potential for chronic inflammation.
- Prunus mume (PM) fruit has known gastrointestinal benefits, but its therapeutic mechanisms are not fully understood.
- Understanding the material basis and mechanisms of PM-EVLPs is crucial for developing novel anti-inflammatory therapies.
Purpose of the Study:
- To investigate the therapeutic effects and underlying mechanisms of Prunus mume-derived EVLPs (PM-EVLPs) in experimental colitis.
- To identify the specific cellular targets and molecular pathways affected by PM-EVLPs.
- To determine the active components within PM-EVLPs responsible for their anti-colitis activity.
Main Methods:
- Oral administration of PM-EVLPs in a mouse model of experimental colitis.
- In vivo bio-distribution analysis to track PM-EVLP localization.
- In vitro studies involving macrophage internalization and clodronate liposome treatment.
- Analysis of inflammasome components (NLRP3, caspase-1), cytokine secretion (IL-1β), and upstream interactions (NEK7-NLRP3).
- RNA sequencing and miRNA mimic/inhibitor assays to identify active RNA molecules.
Main Results:
- Oral PM-EVLPs significantly mitigated experimental colitis in mice.
- PM-EVLPs specifically targeted inflamed colonic tissues and were internalized by macrophages.
- PM-EVLPs selectively inhibited NLRP3 inflammasome activation by disrupting the NEK7-NLRP3 interaction, without affecting other inflammasomes.
- RNA, specifically miR159, was identified as the key component mediating the anti-inflammatory effects.
- PM-EVLPs reduced caspase-1 auto-cleavage and IL-1β secretion.
Conclusions:
- PM-EVLPs are effective nanomedicines for treating colitis, primarily acting through macrophage-mediated inhibition of NLRP3 inflammasome activation.
- The anti-colitis efficacy of PM-EVLPs is attributed to their RNA content, particularly miR159, which targets the NEK7-NLRP3 interaction.
- PM-EVLPs represent a promising, plant-derived therapeutic strategy for inflammatory bowel diseases, warranting further research and development.
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