Mechanistic Underpinnings of Epigenetic Enzyme-Responsive Nanoparticles

Epigenetic enzyme-responsive nanoparticles (ERPs), which destabilize under the influence of histone deacetylase 8 (HDAC8), have been characterized in terms of their physicochemical, nanomechanical, and in vitro attributes. These nanoparticles were synthesized from amphiphilic block copolymers composed of poly(acetyl l-lysine) as the hydrophobic and poly(ethylene glycol) as the hydrophilic block. Upon optimizing the particle assembly process, we demonstrated that the nanoscale properties of ERPs, including hydrodynamic diameter (D_H), size distribution, and stiffness, are selectively influenced by the HDAC8 enzyme. Using ¹H NMR and circular dichroism spectroscopy, we identified that deacetylation of the lysine residues located within the hydrophobic block acts as a molecular driver for the enzyme-induced destabilization of ERPs. Comprehensive in vitro studies demonstrated that ERPs are biocompatible and noncytotoxic and can accumulate in perinuclear and several cellular organelles, including lysosomes and mitochondria. Collectively, this study attempts to establish the mechanistic background of ERP functions, providing the baseline for designing epigenetic-enzyme-sensitive nanoscale platforms.