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一种多功能仿生纳米平台,通过抑制M2巨噬细胞极化,联合免疫检查点阻断用于三阴性乳腺癌免疫治疗。

A multifunctional biomimetic nanoplatform combined with immune checkpoint blockade for triple-negative breast cancer immunotherapy through inhibiting polarization of M2 macrophages.

作者信息

Zhou Qianqian, Jia Zongfang, Mu Yang, Xu Ya, Gao Fang, Wang Ruirui, Gu Liangliang, Liu Feifei, Zhang Sheng, Chen Weidong, Chen Yunna, Wang Lei

机构信息

Anhui University of Chinese Medicine, Hefei, 230012, China.

MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, 230012, China.

出版信息

J Nanobiotechnology. 2025 Aug 18;23(1):569. doi: 10.1186/s12951-025-03663-w.


DOI:10.1186/s12951-025-03663-w
PMID:40826073
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12360003/
Abstract

Immune checkpoint inhibitor (ICI) therapy has become a hopeful treatment for triple-negative breast cancer (TNBC). However, most patients exhibit a low immune response. Tumor-associated fibroblasts (TAFs) suppress anti-tumor immune responses by encouraging the polarization of M2 macrophages, which diminishes the therapeutic efficacy of ICIs. Inhibiting TAFs can reduce the levels of M2 macrophages in the tumor microenvironment, thereby stimulating anti-tumor immune responses. Here, we developed a hybrid membrane-encapsulated biomimetic nanoparticle for inhibiting M2 macrophage polarization. Salvianolic acid B (SAB) was encapsulated in poly(L-lactide-co-glycolide) (PLGA) nanoparticles and coated with a mixed membrane of red blood cells (RBCs) and TAFs on its surface. Nanoparticles coated with RBC membrane possess an "invisible" function that allows them to evade immune clearance and prolong circulation time. When encapsulated by TAF cell membranes, these nanoparticles can precisely target TAFs. By inhibiting TAFs, the released SAB reduced the secretion of CXCL12, thereby interfering with M2 macrophage polarization. In addition, biomimetic nanoparticles increased the levels of CD4 and CD8 T cells within tumors, while reducing the recruitment of myeloid-derived inhibitory cells (MDSCs), ultimately triggering an immune response. When combined with ICIs, biomimetic nanoparticles can extend the survival of mice and dramatically slow the growth of tumors. Our research findings suggest that biomimetic nanoparticles coated with mixed membranes represent an optimal strategy for enhancing the immune response to ICIs.

摘要

免疫检查点抑制剂(ICI)疗法已成为三阴性乳腺癌(TNBC)的一种有前景的治疗方法。然而,大多数患者表现出低免疫反应。肿瘤相关成纤维细胞(TAF)通过促进M2巨噬细胞极化来抑制抗肿瘤免疫反应,这降低了ICI的治疗效果。抑制TAF可以降低肿瘤微环境中M2巨噬细胞的水平,从而刺激抗肿瘤免疫反应。在此,我们开发了一种用于抑制M2巨噬细胞极化的混合膜包裹仿生纳米颗粒。丹酚酸B(SAB)被包裹在聚(L-丙交酯-共-乙交酯)(PLGA)纳米颗粒中,并在其表面涂覆有红细胞(RBC)和TAF的混合膜。涂有RBC膜的纳米颗粒具有“隐形”功能,使其能够逃避免疫清除并延长循环时间。当被TAF细胞膜包裹时,这些纳米颗粒可以精确靶向TAF。通过抑制TAF,释放的SAB减少了CXCL12的分泌,从而干扰了M2巨噬细胞极化。此外,仿生纳米颗粒增加了肿瘤内CD4和CD8 T细胞的水平,同时减少了髓系来源抑制细胞(MDSC)的募集,最终引发免疫反应。当与ICI联合使用时,仿生纳米颗粒可以延长小鼠的生存期并显著减缓肿瘤生长。我们的研究结果表明,涂有混合膜的仿生纳米颗粒是增强对ICI免疫反应的最佳策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/bd44ef8dbaa1/12951_2025_3663_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/1f3817afbbc6/12951_2025_3663_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/5b83b72ea60c/12951_2025_3663_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/073666dc4646/12951_2025_3663_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/ab39b34ae647/12951_2025_3663_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/4292e39149e3/12951_2025_3663_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/209f8d9550f8/12951_2025_3663_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/7166fd770b62/12951_2025_3663_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/0571f8683bee/12951_2025_3663_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/2ef70d2c9e65/12951_2025_3663_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/099ad425cc1c/12951_2025_3663_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/7e8501efaf7b/12951_2025_3663_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/bd44ef8dbaa1/12951_2025_3663_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/1f3817afbbc6/12951_2025_3663_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/5b83b72ea60c/12951_2025_3663_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/073666dc4646/12951_2025_3663_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/ab39b34ae647/12951_2025_3663_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/4292e39149e3/12951_2025_3663_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/209f8d9550f8/12951_2025_3663_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/7166fd770b62/12951_2025_3663_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/0571f8683bee/12951_2025_3663_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/2ef70d2c9e65/12951_2025_3663_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/099ad425cc1c/12951_2025_3663_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/7e8501efaf7b/12951_2025_3663_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6289/12360003/bd44ef8dbaa1/12951_2025_3663_Fig11_HTML.jpg

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