Programmable Encapsulation Enables On‐Demand Proliferation of Therapeutic Bacteria for Potent Cancer Immunotherapy

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Abstract
Engineered bacteria have emerged as a promising therapeutic modality but face safety risks and delivery challenges in clinical practice. Herein, we develop a programmable encapsulation technology that formulates individual bacteria with a thin formulation layer of cross‐linked polymers, which confers live bacteria with reduced immunogenicity and restricted proliferation in healthy organs. To leverage these benefits, an engineered Escherichia coli Nissle strain capable of converting tumor‐accumulated ammonia into L‐arginine and secreting soluble programmed cell death protein 1 (sPD‐1) was encapsulated to synthesize a degradable bacterial capsule, optimizing both biosafety and delivery processes while preserving therapeutic function. Upon reaching the tumors, matrix metalloproteinase‐2 triggers bacterial release and local proliferation, achieving L‐arginine‐driven tumor immune microenvironment modulation and sustained PD‐L1 blockade, ultimately initiating robust antitumor immune responses. Overall, this programmable encapsulation platform tackles both safety risks and delivery challenges of bacterial medicines, broadening the clinical application prospects of live bacterial therapeutics.
Funding Information
  • National Natural Science Foundation of China (52303170)
  • National Natural Science Foundation of China (52525310)
  • National Natural Science Foundation of China (22204001)

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