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基于分级纳米疗法重塑肿瘤免疫微环境并调节T细胞功能以协同抑制骨肉瘤

Reshaping tumor immune microenvironment and modulating T cell function based on hierarchical nanotherapeutics for synergistically inhibiting osteosarcoma.

作者信息

Li Jinsong, Ding Zhiyu, Liu Jieling, Li Guanqi, Li Yuezhan, Wang Weiguo, Nundlall Keshav, Deng Youwen, Miao Jinglei, Hu Meichun, Chen Shijie, Zeng Deliang, Cao Lingyan

机构信息

Department of Spine Surgery, The Third Xiangya Hospital of Central South University, 138 Tongzipo Rd, Changsha, Hunan, 410013, PR China.

Xiangya School of Medicine, Central South University, 172 Tongzipo Rd, Changsha, Hunan, 410078, PR China.

出版信息

Mater Today Bio. 2025 Jul 15;34:102095. doi: 10.1016/j.mtbio.2025.102095. eCollection 2025 Oct.


DOI:10.1016/j.mtbio.2025.102095
PMID:40761512
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12320706/
Abstract

T-cell-based immunotherapy shows significant promise for treating osteosarcoma. However, its effectiveness is often limited by the immunosuppressive tumor environment and weakened T-cell activity. In this study, we present a tumor-targeting strategy that aims to reshape the tumor microenvironment and modulate T-cell function using a hierarchical metal-organic framework (MOF). The MOF is armed with PD-L1 antibody (anti-PD-L1) and loaded with C-C motif chemokine ligand 19 (CCL19) and oxaliplatin in separate layers, which enhances the therapeutic efficiency for osteosarcoma. The intricate hierarchical MOFs employed in this research provide a programmable action schedule for the loaded drugs, enabling spatiotemporal control over their release and action. The anti-PD-L1 on the surface of nanoparticles specifically binds to PD-L1 on tumor cells, reinforcing the targeting and recognition capabilities of the materials. Additionally, this targeted approach serves as an immune checkpoint inhibitors therapy, blocking the binding of PD-1 and PD-L1 between T cells and tumor cells. This prevents T-cell exhaustion, thereby restoring their killing ability. Moreover, the initial release of CCL19 from the nanoparticles recruits more T cells into the tumor microenvironment, augmenting the immunotherapy effect. As a result, when oxaliplatin is pH-responsively released from the nanoparticles upon being absorbed by osteosarcoma cells, it exhibits maximum killing ability against the cancer cells. studies demonstrated that the developed nanosystem exhibited an anti-tumor effect, resulting in a tumor suppression rate exceeding 90 % while causing minimal side effects. This comprehensive approach inhibits tumor growth and metastasis with minimal side effects, demonstrating the positive efficacy of combining immunotherapy and conventional chemotherapy in osteosarcoma treatment. Furthermore, the developed nanoparticles not only have a high drug loading capacity but also prevent mutual interference between different drugs, allowing each drug to exert its optimal effect. This study introduces a promising paradigm for the field of immunochemotherapy and offers potential advancements in the treatment of osteosarcoma.

摘要

基于T细胞的免疫疗法在治疗骨肉瘤方面显示出巨大的前景。然而,其有效性常常受到免疫抑制性肿瘤环境和T细胞活性减弱的限制。在本研究中,我们提出了一种肿瘤靶向策略,旨在利用分级金属有机框架(MOF)重塑肿瘤微环境并调节T细胞功能。该MOF搭载了程序性死亡配体1(PD-L1)抗体(抗PD-L1),并在不同层中分别负载了C-C基序趋化因子配体19(CCL19)和奥沙利铂,从而提高了骨肉瘤的治疗效率。本研究中采用的复杂分级MOF为负载的药物提供了一个可编程的作用时间表,能够对其释放和作用进行时空控制。纳米颗粒表面的抗PD-L1特异性结合肿瘤细胞上的PD-L1,增强了材料的靶向和识别能力。此外,这种靶向方法作为一种免疫检查点抑制剂疗法,阻断了T细胞与肿瘤细胞之间PD-1和PD-L1的结合。这防止了T细胞耗竭,从而恢复它们的杀伤能力。此外,纳米颗粒最初释放的CCL19将更多T细胞募集到肿瘤微环境中,增强了免疫治疗效果。结果,当奥沙利铂被骨肉瘤细胞吸收后从纳米颗粒中pH响应性释放时,它对癌细胞表现出最大杀伤能力。研究表明,所开发的纳米系统具有抗肿瘤作用,肿瘤抑制率超过90%,同时副作用最小。这种综合方法以最小的副作用抑制肿瘤生长和转移,证明了免疫疗法和传统化疗相结合在骨肉瘤治疗中的积极疗效。此外,所开发的纳米颗粒不仅具有高载药量,还能防止不同药物之间的相互干扰,使每种药物都能发挥其最佳效果。本研究为免疫化疗领域引入了一种有前景的范例,并为骨肉瘤治疗提供了潜在的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/f240313235b5/gr8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/cf08258df6cd/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/e4040c128689/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/98be72680996/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/6ed207cf3860/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/85eda08e68a9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/0981328e7aef/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/9342765bd9dc/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/e79dcbc077f9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/f240313235b5/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/25467c57ca76/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/cf08258df6cd/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/e4040c128689/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/98be72680996/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/6ed207cf3860/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/85eda08e68a9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/0981328e7aef/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/9342765bd9dc/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/e79dcbc077f9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8e5/12320706/f240313235b5/gr8.jpg

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本文引用的文献

[1]
Metformin-based nanomedicines for reprogramming tumor immune microenvironment.

Theranostics. 2025-1-1

[2]
Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.

EBioMedicine. 2024-9

[3]
Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy.

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[4]
Correction to "Reversing Chemotherapy Resistance by a Synergy between Lysosomal pH-Activated Mitochondrial Drug Delivery and Erlotinib-Mediated Drug Efflux Inhibition".

ACS Appl Mater Interfaces. 2022-4-27

[5]
Enhancement of anti-PD-1/PD-L1 immunotherapy for osteosarcoma using an intelligent autophagy-controlling metal organic framework.

Biomaterials. 2022-3

[6]
Recent development of metal-organic framework nanocomposites for biomedical applications.

Biomaterials. 2022-2

[7]
New Horizons in the Treatment of Osteosarcoma.

N Engl J Med. 2021-11-25

[8]
Immune-regulating bimetallic metal-organic framework nanoparticles designed for cancer immunotherapy.

Biomaterials. 2022-1

[9]
Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

Br J Cancer. 2022-1

[10]
CCL19 enhances CD8 T-cell responses and accelerates HBV clearance.

J Gastroenterol. 2021-8

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