Targeted V-type peptide-decorated nanoparticles prevent colitis by inhibiting endosomal TLR signaling and modulating intestinal macrophage polarization

内体 巨噬细胞极化 材料科学 巨噬细胞 结肠炎 信号转导 炎症 细胞生物学 免疫学 生物 生物化学 细胞内 体外
作者
Tongxuan Li,Qianqian Li,Sixia Liu,Jiazhu Cao,Jian Mei,Jiameng Gong,Jiugeng Chen,Xiaoyu Wang,Rui Zhang,Xiaomeng Li,Li Wang,Hefan Zhang,Bangmao Wang,Hailong Cao,Hong Yang,Shan‐Yu Fung
出处
期刊:Biomaterials [Elsevier]
卷期号:314: 122843-122843
标识
DOI:10.1016/j.biomaterials.2024.122843
摘要

Inflammatory bowel disease (IBD) has become a serious and challenging health problem globally without curative medical treatments. Mounting evidence suggests that intestinal macrophages and their phenotypes are key players in the pathogenesis of IBD. Modulating the phenotypes and functions of intestinal macrophages through targeted interventions could be a promising approach to manage detrimental gut inflammation in IBD. In this study, we rationally design and fabricate a novel class of V-type peptide-decorated nanoparticles, VP-NP, with potent anti-inflammatory activity. Such a design allows two functional motifs FFD in a single peptide molecule to enhance the bioactivity of the nanoparticles. As expected, VP-NP exhibits a strong inhibitory activity on endosomal Toll-like receptor (TLR) signaling. Surprisingly, VP-NP can inhibit M1 polarization while facilitating M2 polarization in mouse bone marrow-derived macrophages through regulating the key transcription factors NF-κB, STAT1 and PPAR-γ. Mechanistically, VP-NP is internalized by macrophages in the endosomes, where it blocks endosomal acidification to inhibit endosomal TLR signaling; the transcriptomic analysis reveals that VP-NP potently down-regulates many genes in TLR, NF-κB, JAK-STAT, and cytokine/chemokine signaling pathways associated with inflammatory responses. In a colitis mouse model, the intraperitoneally administered VP-NP effectively alleviates the disease activities by decreasing colon inflammation and injuries, pro-inflammatory cytokine production, and myeloid cell infiltration in the gut. Furthermore, VP-NP primarily targets intestinal macrophages and alters their phenotypes from inflammatory M1-type toward the anti-inflammatory M2-type. This study provides a new nanotherapeutic strategy to specifically regulate macrophage activation and phenotypes through a dual mechanism to control gut inflammation, which may augment current clinical treatments for IBD.
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