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Title: Design and Evaluation of Nanoscale Materials with Programmed Responsivity towards Epigenetic Enzymes
Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing ‘intelligent’ encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly (acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles’ hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We further demonstrated the biocompatibility and cellular effects of these materials and conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.  more » « less
Award ID(s):
2239629
PAR ID:
10500916
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ;
Publisher / Repository:
Cold Spring Harbor
Date Published:
Journal Name:
bioRxiv
ISSN:
2692-8205
Subject(s) / Keyword(s):
Nanoparticles, stimuli-responsive nanoparticles, Histone deacetylase, enzyme-responsive nanoparticles, poly (acetyl L-lysine), computer-guided design, protein-ligand docking.
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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