Tumor‐Triggered Disassembly of a Multiple‐Agent‐Therapy Probe for Efficient Cellular Internalization

Integration of multiple agent therapy (MAT) into one probe is promising for improving therapeutic efficiency for cancer treatment. However, MAT probe, if entering the cell as a whole, may not be optimal for each therapeutic agent (with different physicochemical properties), to achieve their best performance, hindering strategy optimization. A peptide‐conjugated‐AIEgen (FC‐PyTPA) is presented: upon loading with siRNA, it self‐assembles into FC siRNA ‐PyTPA. When approaching the region near tumor cells, FC siRNA ‐PyTPA responds to extracellular MMP‐2 and is cleaved into FC siRNA and PyTPA. The former enters cells mainly by macropinocytosis and the latter is internalized into cells mainly through caveolae‐mediated endocytosis. This two‐part strategy greatly improves the internalization efficiency of each individual therapeutic agent. Inside the cell, self‐assembly of nanofiber precursor F, gene interference of C siRNA , and ROS production of PyTPA are activated to inhibit tumor growth.