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

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.