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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cell Biology

Background:

  • Cooperative nanoparticle (NP) internalization is a promising strategy for drug delivery.
  • The role of receptor-targeting in amplifying NP uptake efficiency is not well understood.

Purpose of the Study:

  • To investigate if receptor-targeting ligands can enhance cooperative NP internalization.
  • To elucidate the underlying mechanisms of enhanced NP uptake.

Main Methods:

  • Functionalization of silver NPs with a neuropilin-1 targeting ligand (RPARPAR).
  • Assessment of NP internalization via bystander uptake initiated by TAT-functionalized NPs (T-NPs).
  • Receptor perturbation experiments and coarse-grained molecular dynamics simulations.
  • Analysis of cellular metabolism, specifically extracellular cysteine levels and redox homeostasis.

Main Results:

  • Ligand-modified NPs showed a significant increase in cellular uptake (∼70 units/cell) compared to non-functionalized NPs (∼20 units/cell).
  • Ligand-receptor binding synergizes with membrane mechanics, promoting NP capture in low-energy membrane regions.
  • Extracellular cysteine availability is critical for maintaining cellular redox homeostasis, which regulates macropinocytosis.

Conclusions:

  • Receptor engagement, membrane mechanics, and cellular metabolism converge to drive efficient cooperative NP internalization.
  • This study provides a framework for designing advanced cooperative nanodelivery systems.
  • Findings offer fundamental insights into collective endocytic processes and nanoparticle-cell interactions.