Trigonometric Bundling Disulfide Unit Starship Synergizes More Effectively to Promote Cellular Uptake

Area of Science:

• Biomaterials Science
• Drug Delivery Systems
• Chemical Biology

Background:

• Small molecule disulfide units are promising for cell-surface drug delivery.
• Disulfide bond conformation (dihedral angle) critically impacts drug delivery efficacy and stability.
• Existing disulfide units with low dihedral angles exhibit limited drug delivery potential.

Purpose of the Study:

• To engineer a novel disulfide unit structure for improved drug delivery.
• To investigate the cellular uptake mechanism and efficiency of the new structure.
• To elucidate the molecular interactions driving enhanced membrane permeation.

Main Methods:

• Synthesis of a novel disulfide unit starship using trigonometric bundling on a 3,4,5-trihydroxyphenyl scaffold.
• In vitro assessment of cellular uptake and toxicity.
• Evaluation of the internalization mechanism using thiol erasers.
• Molecular dynamics simulations to analyze membrane interaction and permeation.

Main Results:

• The novel disulfide unit starship demonstrated significantly enhanced cellular uptake (>100x compared to single units) without toxicity.
• Thiol eraser experiments confirmed an endocytosis-independent internalization mechanism mediated by cell-surface thiols.
• Molecular dynamics simulations revealed that starship bundling distorts cell membranes, promoting permeation.

Conclusions:

• Trigonometric bundling of disulfide units effectively overcomes limitations imposed by unfavorable dihedral angles.
• The developed starship system represents a highly efficient and non-toxic platform for drug delivery.
• This approach offers a new strategy for designing advanced drug delivery vehicles based on dynamic covalent chemistry.