# Charge‐Driven Self‐Assembly of Cholesterol Surfactants into Biofunctional Nanodiscs with Antiviral Activity

## TL;DR

Researchers developed cholesterol-based surfactants that self-assemble into nanodiscs with antiviral properties against herpes.

## Contribution

A modular strategy for creating cholesterol surfactants with tunable charges that form antiviral nanodiscs.

## Key findings

- CL-4S surfactants convert lipid vesicles into nanodiscs due to multivalent charges.
- Sulfated nanodiscs and vesicles show inhibitory activity against HSV-1.
- Surface charge control is critical for supramolecular assembly and function.

## Abstract

Self‐assembly of lipid structures derived from amphiphilic molecules plays a crucial role in the development of biomimetic systems. Here we report a modular synthetic strategy for developing cholesteryl‐oligo‐glycerol‐based surfactants with tunable head group functionalities ranging from nonionic to anionic. This approach enables the systematic incorporation of functional groups and thus precise control of surface charge and hydrophilicity. To investigate the influence of multivalent charges on supermolecular‐assembly behavior, we compared three structurally cholesterol (CL) related surfactants: CL‐4S, with four sulfate groups, CL‐1S, with a single sulfate group, and CL‐4OH, a nonionic analog with four hydroxyl groups. We then incorporated these surfactants into lipid bilayers of 1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC) and cholesterol (CL) to study their behavior in membrane‐like environments. Experimental, simulation, and theoretical studies demonstrated that the CL‐4S formulation was able to convert lipid vesicles into nanodiscs, unlike CL‐1S and CL‐4OH, demonstrating the importance of adequate charges in supramolecular transition. Furthermore, both 1S‐Vesicles (CL‐1S based sulfated vesicles) and 4S‐Nanodiscs (CL‐4S based sulfated nanodiscs) showed inhibitory activity against herpes simplex virus‐1 (HSV‐1), indicating the potential of this multivalent supramolecular platform for antiviral applications.

A modular synthesis strategy for cholesterol‐oligo‐glycerol‐based surfactants with tunable nonionic to anionic head groups is reported. The precise control of multivalent surface charges directs self‐assembly and transforms cholesterol vesicles into nanodiscs. Structurally optimized sulfated nanodiscs exhibit significant antiviral activity against HSV‐1. This approach emphasizes the therapeutic potential of charge‐directed supramolecular lipid nanostructures.