Unimer Exchange as a Tool for Programming Enzymatic Degradation through Micellar Dynamics.

Abstract

A key challenge in designing enzyme-responsive micellar nanocarriers lies in balancing their stability and enzymatic degradation. While it has been widely assumed that the micelle-unimer exchange governs enzyme accessibility to the hydrophobic blocks, this relationship had not been directly demonstrated. Here, to uncover this long-assumed mechanistic link, we synthesized a set of triblock amphiphiles that convert by an in situ transition to diblock amphiphiles via reductive cleavage of a central disulfide bond. In parallel, hydrophobicity was independently tuned by modifying the aliphatic end-groups. Enzymatic degradation studies and Förster resonance energy transfer (FRET)-based exchange assays showed two consistent trends across all systems: increasing hydrophobicity led to slower micelle-unimer exchange and reduced enzymatic degradation rates, while transition to diblock consistently enhanced both. These results provide direct evidence that exchange kinetics govern enzymatic degradation and lay the mechanistic foundation for overcoming the stability-degradability barrier for enzyme-responsive micelles by applying architectural transitions as a molecular programming tool.