Receptor Targeting Amplifies Curvature-Driven Cooperative Nanoparticle Internalization under Redox Control

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.