Spatiotemporally Controllable Distribution of Combination Therapeutics in Solid Tumors by Dually Modified Bacteria

Abstract Methods capable of distributing antitumor therapeutics uniformly and durably throughout an entire tumor would be of great significance in maximizing their treatment efficacy, but they have proven to be extremely challenging. Here, bacteria‐mediated spatiotemporally controllable distribution of combination therapeutics in solid tumors is reported to reprogram the immune microenvironment for optimizing antitumor efficacy. By combining synthetic biology and interfacial chemistry, bacteria are inside and outside concurrently modified to express photothermal melanin and to attach immune checkpoint inhibitors on their surface. Due to the nature of bacteria to colonize the hypoxia intratumoral environment, both therapeutic agents can be distributed homogenously and lastingly in tumors during ex vivo human and in vivo mouse studies. Spatiotemporally controllable localization of melanin can repeatedly generate a moderate yet uniform heating of the tumor upon light exposure in a broad treatment window. Combination with similarly localized inhibitors elicits a dual photothermally stimulated and checkpoint‐blockade‐mediated immune activation effect, synergistically reprogramming the immunosuppressive tumor microenvironment. Therapeutic values are demonstrated by significantly inhibited tumor growth and prolonged survival of mice in both subcutaneous and orthotopic murine models. Colonization of dually modified bacteria paves an avenue for spatiotemporally controllable distribution of therapeutic drugs in solid tumors.