The ability of supramolecular assemblies in Nature to alter their structure and function in response to multiple cues in their environment has inspired the development of stimuli-responsive polymeric amphiphiles and assemblies. Among the different types of stimuli, the overexpression of various disease-associated enzymes, makes them highly promising for biomedical applications. Building on our previous research of enzyme-responsive amphiphiles, we will demonstrate that polymeric architecture can be used as a tool for programming formulations to undergo multiple sequential enzymatically induced transition from: (i) micelles to (ii) hydrogel and finally to (iii) dissolved polymers. The reported results demonstrate the ability of using molecular architecture as a modular tool for programming smart formulations to adopt different structures and functions, bringing us closer to the complexity of supramolecular assemblies in Nature.