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Abstract The rational design of materials with cell‐selective membrane activity is an effective strategy for the development of targeted molecular imaging and therapy. Here we report a new class of cationic multidomain peptides (MDPs) that can undergo enzyme‐mediated molecular transformation followed by supramolecular assembly to form nanofibers in which cationic clusters are presented on a rigid β‐sheet backbone. This structural transformation, which is induced by cells overexpressing the specific enzymes, led to a shift in the membrane perturbation potential of the MDPs, and consequently enhanced cell uptake and drug delivery efficacy. We envision the directed self‐assembly based on modularly designed MDPs as a highly promising approach to generate dynamic supramolecular nanomaterials with emerging membrane activity for a range of disease targeted molecular imaging and therapy applications. 

Abstract Many new technologies, such as cancer microenvironment‐induced nanoparticle targeting and multivalent ligand approach for cell surface receptors, are developed for active targeting in cancer therapy. While the principle of each technology is well illustrated, most systems suffer from low targeting specificity and sensitivity. To fill the gap, this work demonstrates a successful attempt to combine both technologies to simultaneously improve cancer cell targeting sensitivity and specificity. Specifically, the main component is a targeting ligand conjugated self‐assembling monomer precursor (SAM‐P), which, at the tumor site, undergoes tumor‐triggered cleavage to release the active form of self‐assembling monomer capable of forming supramolecular nanostructures. Biophysical characterization confirms the chemical and physical transformation of SAM‐P from unimers or oligomers with low ligand valency to supramolecular assemblies with high ligand valency under a tumor‐mimicking reductive microenvironment. The in vitro fluorescence assay shows the importance of supramolecular morphology in mediating ligand–receptor interactions and targeting sensitivity. Enhanced targeting specificity and sensitivity can be achieved via tumor‐triggered supramolecular assembly and induces multivalent ligand presentation toward cell surface receptors, respectively. The results support this combined tumor microenvironment‐induced cell targeting and multivalent ligand display approach, and have great potential for use as cell‐specific molecular imaging and therapeutic agents with high sensitivity and specificity.