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Natural Enzyme-Loaded Polymeric Stealth Coating-Armed Engineered Probiotics by Disrupting Tumor Lactate Homeostasis to Synergistic Metabolism-Immuno-Enzyme Dynamic Therapy.

作者信息

Mao Liuzhou, Xarpidin Bahriman, Shi Rui, Lin Yuting, Hu Haohua, Wu Caisheng, Luo Zheng, Wu Yun-Long

机构信息

State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.

出版信息

Adv Sci (Weinh). 2025 Apr;12(16):e2417172. doi: 10.1002/advs.202417172. Epub 2025 Feb 28.


DOI:10.1002/advs.202417172
PMID:40019380
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12021032/
Abstract

Reducing L-lactate levels in tumors is crucial for alleviating immunosuppression and enhancing treatment efficacy. Recently, bacteria have great potential in improving lactate levels in the tumor microenvironment due to their physiological properties, tumor tropism, and immunogenicity. However, developing bacterial-based lactate regulation platforms is still facing great challenges due to bacterial modification impacts on activity, macrophage phagocytosis, and complex tumor microenvironment. Herein, an engineered Lactobacillus acidophilus (LH@LA) is developed, armed with a polymeric stealth coating that co-loads lactate oxidase (LOx) and horseradish peroxidase (HRP). This coating protects bacteria from macrophage phagocytosis, maintaining their activity for deep tumor drug delivery. And then, LOx and HRP can consume much L-lactate in the tumor site through an enzyme cascade reaction to improve the immunosuppressive environment, while causing oxidative stress and reduced ATP supply, thereby reversing AKT-mTOR metabolic pathway activation to inhibit tumor growth. More interestingly, LA not only acts as a natural enzyme's carrier, but also induces anti-inflammatory M2 macrophages to polarize into pro-inflammatory M1 macrophages by secreting D-lactate, enhancing antitumor immunotherapy. This engineered probiotic design provides a new idea for building a safe and efficient live bacteria delivery platform, providing a reference for developing cancer treatment strategies with clinical translation prospects.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/10fbf1c6a31d/ADVS-12-2417172-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/5bb772220103/ADVS-12-2417172-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/17ad64a6b5f5/ADVS-12-2417172-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/28d7ee93dbb6/ADVS-12-2417172-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/51442f53b932/ADVS-12-2417172-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/4671a8aeeb6b/ADVS-12-2417172-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/d0f52bdcb68c/ADVS-12-2417172-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/941a0ecda181/ADVS-12-2417172-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/10fbf1c6a31d/ADVS-12-2417172-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/5bb772220103/ADVS-12-2417172-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/17ad64a6b5f5/ADVS-12-2417172-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/28d7ee93dbb6/ADVS-12-2417172-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/51442f53b932/ADVS-12-2417172-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/4671a8aeeb6b/ADVS-12-2417172-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/d0f52bdcb68c/ADVS-12-2417172-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/941a0ecda181/ADVS-12-2417172-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b61d/12021032/10fbf1c6a31d/ADVS-12-2417172-g001.jpg

相似文献

[1]
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引用本文的文献

[1]
Mitochondria-Targeted ROS Scavenging Natural Enzyme Cascade Nanogels for Periodontitis Treatment via Hypoxia Alleviation and Immunomodulation.

Adv Sci (Weinh). 2025-8

[2]
Role of gut microbiome in suppression of cancers.

Gut Microbes. 2025-12

本文引用的文献

[1]
Probiotic neoantigen delivery vectors for precision cancer immunotherapy.

Nature. 2024-11

[2]
High-Lactate-Metabolizing Photosynthetic Bacteria Reprogram Tumor Immune Microenvironment.

Adv Mater. 2024-9

[3]
Lithium carbonate revitalizes tumor-reactive CD8 T cells by shunting lactic acid into mitochondria.

Nat Immunol. 2024-3

[4]
Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy.

Adv Mater. 2024-2

[5]
Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.

Cancer Cell. 2023-11-13

[6]
Probiotic-guided CAR-T cells for solid tumor targeting.

Science. 2023-10-13

[7]
d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma.

Sci Adv. 2023-7-21

[8]
Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies.

Clin Cancer Res. 2023-7-5

[9]
Stimuli-Responsive Polymeric Nanovaccines Toward Next-Generation Immunotherapy.

ACS Nano. 2023-6-13

[10]
A probiotic nanozyme hydrogel regulates vaginal microenvironment for vaginitis therapy.

Sci Adv. 2023-5-19

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