RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CXCL10 修饰的热敏“隐形”脂质体用于黑色素瘤的序贯化学免疫治疗
英文原题：CXCL10-coronated thermosensitive "stealth" liposomes for sequential chemoimmunotherapy in melanoma.
查看英文原题
CXCL10-coronated thermosensitive "stealth" liposomes for sequential chemoimmunotherapy in melanoma.
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中文摘要
脂质体-蛋白冠的相互作用因巨噬细胞的主动隔离和血浆快速清除而阻碍了脂质体的临床应用。在此，我们展示了CXCL10作为一种治疗性蛋白被冠状化修饰于热敏脂质体上，形成类隐形纳米载体（CXCL10/TSLs）。通过透明质酸偶联的冬凌草甲素（ORD/CXCL10/TSLs）对CXCL10/TSLs冠状层进行修饰，克服了生物蛋白构建的“流体屏障”，大幅减少了全血中白细胞的捕获，实现了对肿瘤位点的特异性靶向。具有热疗功能的多功能药物ORD/CXCL10/TSLs驱动持续的细胞因子-CXCL10炎症环路，将巨噬细胞表型切换为M1样，扩增肿瘤浸润性NK 细胞，并诱导肿瘤内干扰素-γ水平升高。在ORD/CXCL10/TSLs治疗过程中，冬凌草甲素与CXCL10协同作用，下调PI3K/AKT和Raf/MEK信号通路以促进M1样极化和迁移抑制。
此外，ORD/CXCL10/TSLs在转移性黑色素瘤小鼠中与抗PD-L1抗体有效协同，诱导持久的免疫记忆并控制转移扩散。
展开英文摘要原文
The interplay of liposome-protein corona hinders the clinical application of liposomes due to active macrophage sequestration and rapid plasma clearance.
Here we showed that, CXCL10 as a therapeutic protein was coronated the thermosensitive liposomes to form stealth-like nanocarriers (CXCL10/TSLs). Decoration of the corona layer of CXCL10/TSLs by hyaluronic acid conjugated oridonin (ORD/CXCL10/TSLs), overcame the "fluid barrier" built by biological proteins, drastically reduced capture by leukocytes in whole blood, allowed the specific targeting of tumor sites.
Multifunctional medicine ORD/CXCL10/TSLs with hyperthermia drove the sustained cytokine-CXCL10 inflammatory loop to switch macrophage phenotype to M1-like, expand tumor-infiltrating natural killer cells and induce intratumoral levels of interferon-γ. Oridonin synergized with CXCL10 during ORD/CXCL10/TSLs treatment, downregulated PI3K/AKT and Raf/MEK signaling for M1-like polarization and migration inhibition.
Furthermore, ORD/CXCL10/TSLs potently synergized with anti-PD-L1 antibody in mice bearing metastatic melanoma, induced sustained immunological memory and controlled metastatic spread.
论文信息
- 作者
- Xin X、Zhou Y、Li J、Zhang K、Qin C、Yin L
- 第一作者单位
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xxin@cpu.edu.cn.China
- 通讯作者单位
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China; NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, China; State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lifangyin@cpu.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Nanomedicine : nanotechnology, biology, and medicine2023 Feb
- 原文标识
- PubMed 36462759 · DOI 10.1016/j.nano.2022.102634