Unlocking the enzymatic degradation of polymeric micelles

Enzyme-responsive polymeric micelles hold great potential as drug delivery systems due to the overexpression of disease associated enzymes. To achieve selective and efficient delivery of their therapeutic cargo, the micelles need to be highly stable and yet disassemble when encountering the activating enzyme. While high micellar stability is needed to avoid unwanted premature off-target disassembly and cargo leakage, increasing the stability of the micelles results in drastic decrease in their responsiveness towards enzymatically induced disassembly. The need to balance between stability and enzyme-responsiveness is one of the key challenges towards the translation of enzyme-responsive delivery platforms into therapeutic usage. In our work, we describe a general and modular method for designing highly stable enzyme-responsive polymeric micelles, which their enzyme-responsiveness can be unlocked on demand. The unlocking of the micelles responsiveness towards enzymatic degradation is triggered by an exposure to external stimuli, such as reductive environment or UV radiation. This modular methodology offers a general solution to overcome the stability-responsiveness barrier in enzyme-responsive nano-assemblies, which can potentially be applied to many other self-assembled systems beyond polymeric micelles.