Self-complementary zwitterionic peptides direct nanoparticle assembly and enable enzymatic selection of endocytic pathways

Richard H. Huang, Nazia Nayeem, Ye He, Jorges Morales, Duncan Graham, Rafal Klajn, Maria Contel, Stephen O'Brien, Rein V. Ulijn

Research output: Contribution to journalArticlepeer-review


Supramolecular self-assembly in biological systems holds promise as a means to convert and amplify disease-specific signals to physical or mechanical signals that can direct cell fate. The approach requires programmable self-assembling systems that demonstrate tunable and predictable behavior under physiological conditions. Mixed-charge (zwitterionic) particles are considered suitable for biological applications due to favorable stability. We report on the use of zwitterionic tetrapeptide modalities to direct nanoparticle assembly. These peptides do not form specific folded structures, but they interact through self-complementary patterns of side chain interactions. We demonstrate that the self-assembly can be activated by enzymatic unveiling of zwitterionic LRGD or LRGE modalities through action of matrix metalloprotease-9 (MMP-9), which is over-expressed by cancer cells. Enzymatic activation of gold nanoparticles (AuNPs) decorated with PEGylated peptides ([EG]8-GPKG↓LRGD-[EG]5) reveals LRGD sequences that drive multivalent electrostatic assembly of the nanoparticles, giving rise to robust NP assembly. In the vicinity of cancer cells that over-express MMP-9 enzymes, these aggregates form in proximity of these cells and give rise to 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 NP self-assembly and alter cellular response in biological context.
Original languageEnglish
JournalAdvanced Materials
Publication statusAccepted/In press - 20 Sep 2021


  • enzyme-responsive materials
  • MMP
  • zwitterionic nanoparticles
  • peptides
  • self assembly
  • cellular uptake
  • nanomedicine


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