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Conditional Cell-Penetrating Peptide Exposure as Selective Nanoparticle Uptake Signal.

Melanie Walter1, Merlin Bresinsky2, Oliver Zimmer1

  • 1Department of Pharmaceutical Technology, University of Regensburg, 93053 Regensburg, Bavaria, Germany.

ACS Applied Materials & Interfaces
|July 16, 2024
PubMed
Summary

Researchers developed a novel nanoparticle system for targeted drug delivery. This system uses a conditional cell-penetrating peptide (CPP) mechanism, enhancing uptake by 18-fold in target cells while minimizing side effects.

Keywords:
TATcharge-mediated uptakenanoparticle surface chargenanoparticle targetingpolyargininepolycationicpolymer nanoparticlessequential uptake

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Area of Science:

  • Biotechnology
  • Nanomedicine
  • Drug Delivery

Background:

  • Therapeutic efficacy is limited by low drug concentration at the target site.
  • Nanoparticles (NPs) with cell-targeting ligands improve drug delivery but can trigger unwanted signaling.
  • Cell-penetrating peptides (CPPs) facilitate NP uptake but lack specificity.

Purpose of the Study:

  • To develop a receptor-independent method for conditional nanoparticle (NP) uptake.
  • To achieve targeted NP internalization exclusively into specific cell types.
  • To overcome the limitations of non-specific CPP-mediated NP delivery.

Main Methods:

  • Synthesized core-shell NPs using poly(lactide-co-glycolide) (PLGA) and PLA-PEG block copolymers.
  • Modified NPs with cell-penetrating peptides (CPPs) and an ACE2 inhibitor (MLN-4760).
  • Investigated NP stability, zeta potential, and uptake characteristics in ACE2-expressing cells.

Main Results:

  • Identified TAT47-57 (TAT) as a promising CPP for NP modification.
  • Developed a system where PEG length and MLN-4760 binding conditionally expose CPPs.
  • Achieved an 18-fold increase in NP uptake in ACE2-positive cells compared to unmodified NPs.

Conclusions:

  • Demonstrated a conditional, receptor-independent NP uptake strategy.
  • This approach enhances selectivity and avoids receptor-mediated side effects.
  • Paves the way for improved targeted nanomedicine delivery systems.