Mimovirus Vesicle‐Based Biological Orthogonal Reaction for Cancer Diagnosis

Abstract Herein, a tumor microenvironment (TME)‐responsive mimovirus vesicle (MVV) is engineered to deliver azide motifs (–N 3 ) via the membrane fusion mechanism for cancer diagnosis. As a pH‐responsive functional protein, the spike vesicular stomatitis virus G‐protein (VSVG) is genetically immobilized on surface of cell membrane vesicles. By virtue of the low‐pH activated fusogenic peculiarity of VSVG, the –N 3 groups, which are also presented on MVVs via metabolic engineering, can be directly anchored onto the target cells, thus reducing tumor heterogeneity and serving as the bait to amplify the tumor targeting of dibenzocyclooctyne‐modified diagnostic moieties. The potential diagnostic capability of such design is successfully confirmed in three different murine tumor models. Featuring excellent pH‐sensitive fusogenic traits, the developed MVVs show great responsiveness to the slightly acidic TME of solid tumors, providing a universal platform in overcoming tumor heterogeneity for precise cancer diagnosis.