The Challenge:
Polymeric nanocarriers that can release their covalently attached or encapsulated cargo in response to specific stimuli can offer many advantages such as greater selectivity and consequently reduced side-effects. Among the different types of stimuli-responsive nanocarriers, enzyme-responsive delivery systems can act as a Trojan horse and release their active payload in response to specific disease associated enzymes that are present at the target site.
Despite their enormous potential, the broad applicability of enzyme-responsive nanocarriers has been extremely limited mostly due to the poor accessibility of the activating/degrading enzyme to the hydrophobic domains. This limited accessibility results in the often observed low responsiveness and degradability of stable assemblies.

Technology description: 
To solve this fundamental barrier, our molecular approach applies a a dual-step activation mechanism to triggers a macromolecular architectural transition at the first stage , followed by complete enzymatic degradation of the nanocarrier in the second stage. Based on more than a decade of studying enzyme-responsive polymeric assemblies, we can design tri-block amphiphiles (hydrophobic-hydrophilic-hydrophobic) and formulate them into highly stable polymeric assemblies. Introduction of a cleavable group exactly at the center of the hydrophilic block allows for a stimuli-induced architectural transition of the tri-block amphiphile into two di-block amphiphiles (hydrophobic-hydrophilic) having the same hydrophilic to lipophilic ratio as the parent tri-block amphiphile. This architectural transition has minimal effect on the thermodynamic stability of the nanocarriers but it affects their kinetic stability making them significantly more reactive towards enzymatic degradation, leading to the complete disassembly of the nanocarrier and release of its therapeutic cargo.
The high modularity of this approach can allow different combination of cleavable linkers, hydrophilic block, and enzyme-responsive hydrophobic blocks in order to tailor the nanocarrier and its release mechanism to the specific conditions at the target site of disease.