A Bioorthogonal and Programmable Bacterial Delivery System for Spatiotemporally Targeted Therapy of Solid Tumors

ABSTRACT Rapid advances in synthetic biology are driving the development of microbes as therapeutic agents. While the immunosuppressive tumor microenvironment creates a favorable niche for the systematic delivery of bacteria and therapeutic payloads, these can be harmful if released into healthy tissues. To address this limitation, we designed a spatiotemporal targeting system for engineered Escherichia coli Nissle 1917, controlled by azide‐modified hyaluronic acid hydrogel and near‐infrared radiation induction. Using a temperature‐driven genetic status switch, the system produced durable therapeutic output and promoted the therapeutic activity in solid tumors. The combination of azide‐modified hyaluronic acid hydrogel and temperature‐sensitive, engineered Escherichia coli Nissle 1917 provided spatiotemporal targeting of solid tumors, not only showing significant therapeutic effects on primary solid tumors, but also inhibiting the metastasis and recurrence of cancer cells by enhancing tumor‐infiltrating lymphocytes. This system has potential for clinical application.