Interleukin-2 (IL-2) immunotherapy has considerable potential in the treatment of metastatic cancers; however, its efficacy is limited by low response rates, dose-dependent toxicity, short half-life, poor tumor accumulation, and non-targeted immune activation. This study introduces a biohybrid micro-robot (IL-2@Z/C/A), which is engineered by mimicking mineralization of IL-2 variant secretion by Escherichia coli Nissle 1917 (EcN), with a zeolite-based pyroparaffin framework-8 (ZIF-8) as the shell, and supplemented with aggregation-induced emission photosensitizer and catalase. The ZIF-8 coating prevents premature drug leakage and systemic exposure while maintaining the tumor-targeting ability of the bacteria, thereby minimizing off-target effects. When the framework accumulates in the acidic tumor microenvironment (TME), it degrades to release the engineered bacteria and therapeutic substances. Local release of zinc ions, photo-induced reactive oxygen species, and the EcN-derived pathogen-associated molecular patterns synergistically induce flame erosion mediated by Cle-caspase/GSDMD, leading to immune cell death, accompanied by the release of damage-associated molecular patterns and the production of pro-inflammatory cytokines. Simultaneously, hydrogen peroxide-driven oxygen generation alleviates hypoxia and inhibits HIF-1α-induced immunosuppression. Combined with PD-L1 blockade, IL-2@Z/C/A achieves nearly complete tumor regression in the B16F10 melanoma model through coordinated immune cascades: thermal interaction-mediated antigen exposure activates adaptive immunity, hypoxia reversal counteracts immunosuppression, continuous local IL-2 release reverses T cell exhaustion, overall reprogramming of the immunosuppressive TME, and induces strong anti-tumor immunity. This work establishes a unique paradigm for spatially controlled immunotherapy and highlights the potential of this biohybrid micro-robot to transform immunologically "cold" tumors into responsive ecological niches. This study was published in ACS Nano under the title "Engineered Bacteria-Driven Biohybrid Microrobots Enhance IL-2 Immunotherapy by Triggering Pyroptosis".
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DOI: 10.1021/acsnano.5c21475