# Flipper dendrimers

## TL;DR

Scientists developed improved fluorescent probes called flipper dendrimers that reduce phototoxicity and allow longer imaging of cell membrane forces.

## Contribution

Flipper dendrimers reduce phototoxicity while maintaining membrane tension responsiveness through supramolecular chemistry strategies.

## Key findings

- Flipper dendrimers enable imaging at lower laser power, reducing phototoxicity.
- Peptide dendrimers improve probe integration into membranes, enhancing fluorescence.
- The strategy is generally applicable for fluorescent probe design.

## Abstract

Fluorescent flippers have been introduced as small-molecule probes to image physical forces within cell membranes. Despite their popularity and much effort, significant improvements of performance have not been reported since their first design. Now, almost a decade after their introduction, we disclose flipper dendrimers that address the main practical problem with flipper probes: phototoxicity. Flipper dendrimers provide much stronger fluorescence in cells while maintaining responsiveness to changes in membrane tension. This increased effective brightness enables imaging at almost one order of magnitude lower laser power to generate the same fluorescence intensity, thereby reducing phototoxicity and allowing longer monitoring of biological processes. This breakthrough is achieved using large peptide dendrimers that maximize deliverability as Israelachvili-inspired inverted cones. Peptide dendrimers and hydrophobic interfacers modulate fluorescence lifetime and plasma membrane targeting by controlling probe orientation, interdomain distribution, intermembrane transfer and internalization. This supramolecular chemistry strategy to improve performance by engineering probe integration into the environment, rather than the mechanophore itself, is generally applicable.

Shifting focus from mechanophore engineering to deliverability and interfacing affords fluorescent probes with higher effective brightness and lower phototoxicity for the imaging of membrane tension in living cells over longer periods of time.