Engineered Bacteria-Driven Biohybrid Microrobots Potentiate IL-2 Immunotherapy by Evoking Pyroptosis

Area of Science:

• Biomedical Engineering
• Cancer Immunotherapy
• Nanotechnology

Background:

• Interleukin-2 (IL-2) immunotherapy shows promise for metastatic cancers but faces limitations like toxicity and poor tumor targeting.
• Existing immunotherapies struggle with low response rates and systemic side effects.

Purpose of the Study:

• To develop a biohybrid microrobot (IL-2@Z/C/A) for targeted and enhanced cancer immunotherapy.
• To overcome the limitations of traditional IL-2 therapy by improving drug delivery and reducing off-target effects.

Main Methods:

• Engineered a biohybrid microrobot using IL-2 variant-secreting *Escherichia coli* Nissle 1917 (EcN) coated with zeolitic imidazolate framework-8 (ZIF-8).
• The microrobot was coloaded with a photosensitizer and catalase, designed to release cargo in the acidic tumor microenvironment (TME).
• Investigated synergistic effects of pyroptosis induction, oxygen generation, and PD-L1 blockade in a B16F10 melanoma model.

Main Results:

• The ZIF-8 shell protected bacteria and cargo, enabling tumor homing and controlled release in the TME.
• IL-2@Z/C/A induced pyroptosis, immunogenic cell death, and pro-inflammatory cytokine production.
• Catalase activity generated oxygen, alleviating tumor hypoxia and immunosuppression, while IL-2 release reversed T cell exhaustion.
• Combination therapy achieved near-complete tumor regression by reprogramming the immunosuppressive TME and eliciting strong antitumor immunity.

Conclusions:

• The biohybrid microrobot (IL-2@Z/C/A) offers a novel strategy for spatially controlled cancer immunotherapy.
• This approach effectively converts immunologically 'cold' tumors into responsive niches, highlighting potential for enhanced antitumor responses.