Low-pH preconditioned macrophage-derived extracellular vesicles enable targeted and enhanced paclitaxel therapy in gastric cancer

doi:10.4251/wjgo.v18.i6.117697

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World Journal of Gastrointestinal Oncology

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1948-5204

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. Jun 15, 2026; 18(6): 117697
Published online Jun 15, 2026. doi: 10.4251/wjgo.v18.i6.117697

Low-pH preconditioned macrophage-derived extracellular vesicles enable targeted and enhanced paclitaxel therapy in gastric cancer

Jing-Hui Wang, Ming-Li Hu, Min Shi, Jia-Li Ma, Jing Yang, Yu-Gang Wang

Jing-Hui Wang, Ming-Li Hu, Min Shi, Jia-Li Ma, Yu-Gang Wang, Department of Gastroenterology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China

Jing Yang, Department of Pathology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China

Yu-Gang Wang, Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China

Co-first authors: Jing-Hui Wang and Ming-Li Hu.

Co-corresponding authors: Jing Yang and Yu-Gang Wang.

Author contributions: Wang JH and Hu ML contributed equally to this work as co-first authors; Wang JH and Hu ML were responsible for the study conception and design, performed the majority of experiments, analyzed the data, and drafted the initial manuscript; Shi M and Ma JL participated in experimental execution, data collection, and data organization; Yang J and Wang YG provided overall experimental guidance and research resources, supervised the project, critically revised and proofread the manuscript, and contributed equally as co-corresponding authors; and all authors reviewed and approved the final manuscript.

Supported by Natural Science Foundation of the Science and Technology Commission of Shanghai Municipality, No. 23ZR1458300 (to Wang YG); Key Discipline Project of Shanghai Municipal Health System, No. 2024ZDXK0004 (to Shi M); Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission, No. 20254Y0097 (to Wang JH); Youth Project Fund of Changning District Health Commission, No. 2024QN02 (to Wang JH); and Research Fund of Key Laboratory for Translational Research and Innovative Therapeutics of Gastrointestinal Oncology, No. ZDSYS-2023-04 (to Wang JH).

Institutional animal care and use committee statement: This study was performed in strict accordance with the Regulations for the Care and Use of Laboratory Animals and the Guidelines for Ethical Review of Animal Experiments (China, GB/T 35892-2018). All procedures involving animals were reviewed and approved by Ethics Committee of Shanghai Tong Ren Hospital (approval number: A2023-004-01).

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: Dataset available from the corresponding author at wyg0061@shtrhospital.com.

Corresponding author: Yu-Gang Wang, MD, Professor, Department of Gastroenterology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111 Xianxia Road, Changning District, Shanghai 200336, China. wyg0061@shtrhospital.com

Received: December 24, 2025
Revised: January 21, 2026
Accepted: February 25, 2026
Published online: June 15, 2026
Processing time: 176 Days and 0.8 Hours

Abstract

BACKGROUND

Gastric cancer remains a major cause of cancer-related mortality worldwide, and traditional chemotherapy is frequently limited by poor tumor targeting, off-target toxicity, and insufficient combined therapeutic benefit. Emerging evidence suggests that tumor microenvironmental cues, particularly the acidic condition, can enhance the tumor-targeting capacity and modulate the bioactive cargo of extracellular vesicles (EVs) derived from certain cell types. However, whether low-pH preconditioned macrophage-derived EVs (LP-EV) acquire enhanced tumor-targeting properties and intrinsic anti-tumor activity, as well as the underlying mechanisms, remains largely unknown.

AIM

To investigate tumor targeting and intrinsic bioactivity of LP-EV, and their combined therapeutic effects with paclitaxel (PTX) in gastric cancer.

METHODS

LP-EV were isolated from J774.1 macrophages cultured at pH 6.5 and systematically characterized in comparison with control EVs (C-EV). Tumor-targeting performance was evaluated using cellular uptake assays and in vivo fluorescence imaging. miRNA profiles of LP-EV and C-EV were analyzed by sequencing. PTX-loaded LP-EV (PTX@LP-EV) were prepared via sonication, and their anti-tumor effects were assessed in vitro and in MKN45 gastric cancer xenograft models. Tumor transcriptome sequencing was conducted to elucidate mechanisms associated with the enhanced anti-tumor effects.

RESULTS

LP-EV exhibited significantly enhanced tumor-targeting ability compared with C-EV. miRNA sequencing revealed that LP-EV were selectively enriched in miRNAs with previously reported anti-tumor activities. PTX@LP-EV exhibited markedly superior anti-tumor efficacy compared with free PTX, accompanied by pronounced tumor growth inhibition. Transcriptome analysis revealed that PTX@LP-EV induced a distinct transcriptional profile compared to free PTX, and gene set enrichment analysis indicated the engagement of cooperative biological pathways consistent with enhanced therapeutic effects. A miRNA-target gene regulatory network analysis suggested that LP-EV-derived miRNAs may contribute to the remodeling of tumor survival and stress-response networks, thereby suggesting a potential molecular basis for the observed combination therapeutic effects.

CONCLUSION

Low-pH preconditioning confers macrophage-derived EVs with improved tumor-targeting capability and intrinsic anti-tumor activity. PTX@LP-EV achieve enhanced anti-tumor efficacy through coordinated, multi-level transcriptional reprogramming in gastric cancer.

Keywords: Extracellular vesicles; Low-pH preconditioning; Targeted delivery; Combined therapy; Gastric cancer

Core Tip: In this study, we report a microenvironment-inspired strategy to customize macrophage-derived extracellular vesicles (EVs) through low-pH preconditioning, mimicking the acidic characteristics of the tumor microenvironment. This approach markedly enhances EVs' tumor targeting and endows them with a distinct miRNA cargo associated with reported anti-tumor functions. When used as nanocarriers for paclitaxel (PTX), the resulting biomimetic system (PTX@LP-EV) achieves superior anti-tumor efficacy in gastric cancer models. Mechanistically, EV-borne miRNAs induced by tumor microenvironmental stimulation may cooperatively suppress pro-tumorigenic genes, which is consistent with the observed enhanced therapeutic effects.