Spatiotemporal Delivery of Dual Nanobodies by Engineered Probiotics to Reverse Tumor Immunosuppression via Targeting Tumor-Derived Exosomes

The anti-PD-L1 and its bispecific antibodies have exhibited durable antitumor immunity but still elicit immunosuppression mainly caused by tumor-derived exosomes (TDEs), leading to difficulty in clinical transformation. Herein, engineered Escherichia coli Nissle 1917 (EcN) coexpressing anti-PD-L1 an...

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Bibliographic Details
Published in:ACS nano 2024-10, Vol.18 (39), p.26858-26871
Main Authors: Qin, Shurong, Liu, Yuta, He, Guanzhong, Yang, Jingjing, Zeng, Fei, Lu, Qianglan, Wang, Meng, He, Bangshun, Song, Yujun
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
B7-H1 Antigen - antagonists & inhibitors
B7-H1 Antigen - immunology
B7-H1 Antigen - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Escherichia coli - genetics
Exosomes - chemistry
Exosomes - immunology
Exosomes - metabolism
Humans
Immunotherapy
Indocyanine Green - chemistry
Metal-Organic Frameworks - chemistry
Metal-Organic Frameworks - pharmacology
Mice
Neoplasms - immunology
Neoplasms - pathology
Neoplasms - therapy
Probiotics
Single-Domain Antibodies - chemistry
Single-Domain Antibodies - immunology
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Summary:The anti-PD-L1 and its bispecific antibodies have exhibited durable antitumor immunity but still elicit immunosuppression mainly caused by tumor-derived exosomes (TDEs), leading to difficulty in clinical transformation. Herein, engineered Escherichia coli Nissle 1917 (EcN) coexpressing anti-PD-L1 and anti-CD9 nanobodies (EcN-Nb) are developed and decorated with zinc-based metal–organic frameworks (MOFs) loaded with indocyanine green (ICG), to generate EcN-Nb-ZIF-8CHO-ICG (ENZC) for spatiotemporal lysis of bacteria for immunotherapy. The tumor-homing hybrid system can specifically release nanobodies in response to near-infrared (NIR) radiation, thereby targeting TDEs and changing their biological distribution, remodeling tumor-associated macrophages to M1 states, activating more effective and cytotoxic T lymphocytes, and finally, leading to the inhibition of tumor proliferation and metastasis. Altogether, the microfluidic-enabled MOF-modified engineered probiotics target TDEs and activate the antitumor immune response in a spatiotemporally manipulated manner, offering promising TDE-targeted immune therapy.
ISSN:1936-0851
1936-086X
1936-086X
DOI:10.1021/acsnano.4c08117