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  3. Precision tumor immunotherapy via a dual-gated macrophage-bacterial activation platform

Precision tumor immunotherapy via a dual-gated macrophage-bacterial activation platform

  • Trends Biotechnol. 2025 Oct 30:S0167-7799(25)00401-9. doi: 10.1016/j.tibtech.2025.09.013.
Lin Li 1,  Leyang Wu 2,  Liyuan Qiao 1,  Shuhui Zhang 1,  Xiaowei Luan 3,  Jiahui Qiu 1,  Xinyue Qiao 1,  Chenyang Li 1,  Ying Sun 1,  Bohao Wang 1,  Zengzheng Du 1,  Xiaoyao Chang 1,  Hongqin Zhuang 1,  Tao Zhang 4,  Yanlong Jia 4,  Tianyun Wang 4,  Wenjie Ren 4,  Yujun Song 5,  Zichun Hua 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023. Jiangsu, PR China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023. Jiangsu, PR China; Nanjing Generecom Biotechnology Co., Ltd, Nanjing 210023, Jiangsu, PR China; Changzhou High-Tech Research institute of Nanjing University and Jiangsu TargetPharma Laboratories, Inc., Changzhou 213164, Jiangsu, PR China. Electronic address: lywu@nju.edu.cn.
  • 3 College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, National Laboratory of Solid State Microstructures, Nanjing University, Nanjing, 210023, Jiangsu, PR China.
  • 4 Faculty of Pharmaceutical Sciences, Xinxiang Medical University, Xinxiang 453002, Henan, PR China.
  • 5 College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, National Laboratory of Solid State Microstructures, Nanjing University, Nanjing, 210023, Jiangsu, PR China. Electronic address: ysong@nju.edu.cn.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023. Jiangsu, PR China; Nanjing Generecom Biotechnology Co., Ltd, Nanjing 210023, Jiangsu, PR China; Changzhou High-Tech Research institute of Nanjing University and Jiangsu TargetPharma Laboratories, Inc., Changzhou 213164, Jiangsu, PR China; Faculty of Pharmaceutical Sciences, Xinxiang Medical University, Xinxiang 453002, Henan, PR China; School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, PR China. Electronic address: zchua@nju.edu.cn.
PMID: 41173725 DOI: 10.1016/j.tibtech.2025.09.013
Abstract

Immunotherapy based on live Microorganisms has shown promise in preclinical studies, but its clinical translation has been hampered by limited efficacy and non-negligible toxicity. Here, we developed Macrophage-Bacteria encapsulation Lytic Autoactivated Synergistic Therapeutics (M-BLAST), a dual-gated macrophage-mediated Bacterial tumor-targeted delivery and in situ activation system. M-BLAST incorporates density-regulated virulence-enhanced attenuated Salmonella strains as the therapeutic core, thermally controlled gasdermin D N-terminal fragment (GSDMD-N)-expressing macrophages as the delivery vector, and copper selenide, a photothermal material, as a heat shock 'primer'. Following systemic administration, localized near-infrared (NIR) irradiation at the tumor site triggers macrophage Pyroptosis, ensuring rapid and complete Bacterial release. This disrupts the immunosuppressive tumor microenvironment (TME) and elicits a widespread cascading antitumor response, just like a 'immune bomb', while the dual-gating design of Bacterial density and heat shock ensures safety by preventing off-target activation in non-tumor regions. Thus, M-BLAST could enhance the therapeutic utility of living engineered bacteria for Cancer while ensuring safety for patients.

Keywords

attenuated Salmonella; cell-mediated drug delivery; drug controlled release; macrophage; microbial therapeutics; synthetic biology.

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