A central challenge in cancer care is to ensure that therapeutic compounds reach their targets. One approach is to use enzyme-responsive biomaterials, which reconfigure in response to endogenous enzymes that are overexpressed in diseased tissues, as potential site-specific anti-tumoral therapies. Here we report peptide micelles that upon MMP-9 catalyzed hydrolysis reconfigure to form fibrillar nanostructures. These structures slowly release a doxorubicin payload at the site of action. Using both in vitro and in vivo models, we demonstrate that the fibrillar depots are formed at the sites of MMP-9 overexpression giving rise to enhanced efficacy of doxorubicin, resulting in inhibition of tumor growth in an animal model.

Over-expression and activation of matrix metalloproteinase-9 (MMP-9) is associated with multiple diseases, and can serve as a stimulus to activate nanomaterials for sensing and controlled release. In order to achieve autonomous therapeutics with improved space-time targeting capabilities, several features need to be considered beyond the introduction of an enzyme-cleavable linker into a nanostructure. We introduce guiding principles for a customizable platform using supramolecular peptide nanostructures with three modular components to achieve tunable kinetics and morphology changes upon MMP-9 exposure. This approach enables: (1) fine-tuning of kinetics through introduction of ordered/disordered structures, (2) a 12-fold variation in hydrolysis rates achieved by electrostatic (mis) matching of particle and enzyme charge, and (3) selection of enzymatic reaction products that are either cell-killing nanofibers or that disintegrate. These guiding principles, which can be rationalized and involve exchange of just a few amino acids, enable systematic customization of enzyme-responsive peptide nanostructures for general use in performance optimization of enzyme-responsive materials.