Self‐Complementary Zwitterionic Peptides Direct Nanoparticle Assembly and Enable Enzymatic Selection of Endocytic Pathways

Abstract

Supramolecular self‐assembly in biological systems holds promise to convert and amplify disease‐specific signals to physical or mechanical signals that can direct cell fate. However, it remains challenging to design physiologically stable self‐assembling systems that demonstrate tunable and predictable behavior. Here, the use of zwitterionic tetrapeptide modalities to direct nanoparticle assembly under physiological conditions is reported. The self‐assembly of gold nanoparticles can be activated by enzymatic unveiling of surface‐bound zwitterionic tetrapeptides through matrix metalloprotease‐9 (MMP‐9), which is overexpressed by cancer cells. This robust nanoparticle assembly is achieved by multivalent, self‐complementary interactions of the zwitterionic tetrapeptides. In cancer cells that overexpress MMP‐9, the nanoparticle assembly process occurs near the cell membrane and causes size‐induced selection of cellular uptake mechanism, resulting in diminished cell growth. The enzyme responsiveness, and therefore, indirectly, the uptake route of the system can be programmed by customizing the peptide sequence: a simple inversion of the two amino acids at the cleavage site completely inactivates the enzyme responsiveness, self‐assembly, and consequently changes the endocytic pathway. This robust self‐complementary, zwitterionic peptide design demonstrates the use of enzyme‐activated electrostatic side‐chain patterns as powerful and customizable peptide modalities to program nanoparticle self‐assembly and alter cellular response in biological context.

The Impact of Tyrosine Iodination on the Aggregation and Cleavage Kinetics of MMP-9-Responsive Peptide Sequences

“…Huang et al recently demonstrated the MMP-9-triggered assembly of gold nanoparticles via electrostatic interactions following MMP-mediated dePEGylation. These nanoparticles underwent endocytosis and induced cytotoxicity in the MMP-9-expressing cells where inverting just two amino acids in this sequence inactivated the enzyme-responsiveness, self-assembly, and cellular uptake . Enzyme-directed nanoparticle self-assembly at a tumor site was also used for in vivo cancer imaging based on kinetic trapping of the assembled particles within the tumor .…”

Systems chemistry of peptide-assemblies for biochemical transformations

“…The design of active sites based on artificial systems via using the concept of supramolecular assembly is the key to gain further insight into the natural evolution of enzymes. [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] 2.1 Peptide based self-assembly as esterase Esterase and in particular carbonic anhydrases (CAs) are among the ubiquitous metalloenzymes that regulate various physiological functions along with implications in the field of biotechnology. [72][73][74] Despite numerous efforts for artificially fabricating CA mimics, the complex folding patterns and the stability of the peptide building blocks pose tremendous hurdles.…”

“…The design of active sites based on artificial systems via using the concept of supramolecular assembly is the key to gain further insight into the natural evolution of enzymes. 53–71…”

Responsive Hydrogels Based on Triggered Click Reactions for Liver Cancer

“…[32] Copyright 2021, The Royal Society of Chemistry. Internal stimuli pH-responsive PEG, TEG Inward diffusion [47,100,118,123,126,129] Redox-responsive PEG Inward diffusion [56,136,156] Enzyme-responsive ALG Cross-linking-codependent [14,27,106,124,130,132,158] Electroresponsive PLGA, PEG Inward diffusion [70,146,196] ROS-responsive PEG, PLGA Self-assembled [149,150,160,162,165] External stimuli Thermoresponsive PEG, PLGA In situ formation [7,30,34,42,67,170,171,173,175,17 8,181] Light-responsive PLGA, ALG Self-assembled [9,28,113,183,185] Magnetic-responsive ALG, HA Cross-linking-codependent [29,166,193,194,195] Mechanoresponsive PEG, PCL Inward diffusion [146,148,197,199,200] Ultrasound-responsive PEG Inward diffusion [14,163,201,…”