In recent years, the increasing application of nanomaterials in the medical, food additives, and drug delivery fields is attributed to their unique physical and chemical properties, particularly their significant potential in drug delivery, disease diagnosis, and treatment. As a critical immune organ and barrier in the human body, the intestine plays a vital role in defending against harmful external factors. Toll-like receptor 4 (TLR4) expressed on intestinal cells is essential for maintaining intestinal barrier function and modulating immune responses. Studies have indicated that nanoparticles (NPs) can directly interact with intestinal cells upon entering the intestine, stimulating the TLR4 signaling pathway and initiating a cascade of biological reactions, including inflammation, autophagy, and immune dysregulation. Aberrant activation of TLR4 exacerbates the disruption of the intestinal microenvironment, potentially contributing to systemic inflammatory diseases. This process involves mechanisms such as the secretion of pro-inflammatory factors and recruitment of immune cells, ultimately resulting in intricate toxic effects, including impairment of intestinal barrier function. However, current research predominantly focuses on canonical TLR4 signaling, yet key NPs-specific molecular mechanisms remain poorly understood at the single-cell level. However, despite numerous studies on NPs-TLR4 interactions, the lack of systematic summaries and in-depth analysis has led to unclear mechanisms and conflicting findings. This review aims to comprehensively examine the regulatory effects of NPs on the TLR4 signaling pathway and investigate their toxicological implications on intestinal barrier dysfunction. The objective is to offer novel insights and theoretical foundations for future research on the mechanisms underlying NP-induced intestinal injury.
Keywords: TLR4; gut microbiota; intestinal barrier; intestinal injury; nanoparticles.
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