Octopus-inspired engineered bacteria with a plug-and-play surface display system achieves enhanced tumor-specific colonization and antitumor immunity

Le-Yang Wu; Jia-Hui Qiu; Xin-Yue Qiao; Lin Li; Li-Yuan Qiao; Chen-Yang Li; Ying Sun; Shu-Hui Zhang; Zeng-Zheng Du; Xiao-Yao Chang; Cheng Cheng; Bo-Hao Wang; Yi-Han Xiao; Lin Lin; Zi-Chun Hua

doi:10.1016/j.mmr.2026.100030

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Octopus-inspired engineered bacteria with a plug-and-play surface display system achieves enhanced tumor-specific colonization and antitumor immunity

RESEARCH | Updated：2026-05-11

- Octopus-inspired engineered bacteria with a plug-and-play surface display system achieves enhanced tumor-specific colonization and antitumor immunity
- Military Medical Research (2026)
- Affiliations：
  
  State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China
  Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories, Inc., Changzhou 213164, Jiangsu, China
  School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
  School of Food and Biological Engineering, Jiangsu University, Nanjing 212013, China
  Faculty of Pharmaceutical Sciences, Xinxiang Medical University, Xinxiang 453002, Henan, China
- Author bio：
  
  *Le-Yang Wu, lywu@nju.edu.cn;
  Lin Lin, linl@ujs.edu.cn;
  Zi-Chun Hua, zchua@nju.edu.cn
- Funds：
- DOI：10.1016/j.mmr.2026.100030
  CLC：
- Received：21 June 2025，
  
  Accepted：03 April 2026，
  
  Published：2026-04
- Accepted：
Scan QR Code
Wu LY, Qiu JH, Qiao XY, Li L, Qiao LY, Li CY, et al. Octopus-inspired engineered bacteria with a plug-and-play surface display system achieves enhanced tumor-specific colonization and antitumor immunity. Mil Med Res. 2026;13(1):100030.
DOI：

Wu LY, Qiu JH, Qiao XY, Li L, Qiao LY, Li CY, et al. Octopus-inspired engineered bacteria with a plug-and-play surface display system achieves enhanced tumor-specific colonization and antitumor immunity. Mil Med Res. 2026;13(1):100030. DOI： 10.1016/j.mmr.2026.100030.

摘要

Abstract

Background:

Bacteria-mediated cancer therapy leverages bacteria to modulate the tumor immune microenvironment and deliver therapeutics. However

its clinical application is limited by toxicity

off-target effects

and uncontrolled drug release. Improving tumor targeting and precise payload delivery through rational bacterial engineering is essential for increasing efficacy and safety.

Methods:

An attenuated

Salmonella ΔhtrA::luxI

-VNP20009 strain expressing OmpA-SpyTag (AISI-ST) was constructed for the modular surface conjugation of SpyCatcherΔ (SC)-fused quadruple arginine-glycine-aspartic acid (RGD) peptides (named AISI-ST/SC-RGD×4) and for building biointerfaces for enhanced tumor adhesion via RGD-mediated integrin αvβ3 interactions. The tumor-bearing mice received intravenous injections of AISI-ST/SC-RGD×4

and their biodistribution was analyzed using bioluminescence imaging and colony-forming unit (CFU) counts. Quorum-sensing (QS)-regulated high-temperature requirement A (HtrA) and anti-programmed cell death protein 1 (anti-PD1) nanobody expression based on the

LuxI

promoter in strains was validated by Western blotting. Immune responses were assessed using flow cytometry.

Results:

The incubation of the fused proteins with the AISI-ST strain for 1 h was sufficient to form a stable biological

interface. The quadruple RGD-modified bacteria (AISI-ST/SC-RGD×4) exhibited greater enrichment in various solid tumors and lung metastases with reduced off-target accumulation. QS induced the expression of the HtrA protein within tumors

resulting in enhanced extracellular polysaccharide-mediated immunogenicity to activate immune cells. Further expression of anti-PD1 nanobodies synergistically enhanced antitumor immunity

increasing the percentage of M1 macrophages (MACS) and CD8

T cell proliferation while suppressing M2 MACS and regulatory T cells (Tregs). This approach achieves potent tumor suppression via targeted immune remodeling.

Conclusions:

This study presents octopus-inspired engineered bacteria with a “plug-and-display” system and tumor-specific drug delivery that achieves enhanced tumor targeting and potent antitumor effects. This study describes a promising strategy for the precise and safe clinical translation of bacteria-mediated cancer immunotherapy.

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references

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