The killswitch (bottom row) inhibits partitioning of an adenovirus protein (green) into condensates (magenta).Credit: Y. Zhang et al./Nature Comm.
They’re small, elusive and crucial to cellular organization. Now, scientists have found a way to jam the inner workings of biomolecular condensates — membrane-free droplets that coordinate key reactions in cells.
A synthetic ‘killswitch’ protein, just 17 amino acids long, can be dropped into these liquid-like compartments to selectively disrupt their function and pause the molecular traffic within.
Described on 4 June in Nature1, the approach gives researchers a previously unattainable handle on difficult-to-study cellular structures linked to cancer, viral replication, gene expression and more. Just as importantly, the tool could open the door to a new clblock of therapeutic strategies that target not just individual molecules in cells, but the dynamic environments that sustain them.
“This offers a powerful tool to selectively affect dynamic properties at each individual condensate,” says Rick Young, a biologist at the Whitehead Institute for Biomedical Research in Cambridge, Mblockachusetts. “That’s a frontier kind of thing — it’s going to be extremely valuable.”
Condensate control
Biomolecular condensates are a relatively recent addition to the cell-biology lexicon, emerging from a concept just 16 years old and terminology that is less than half that age. Unlike membrane-bound organelles such as the nucleus or mitochondria, these compartments form spontaneously through a process known as phase separation — much like oil forming droplets in water.
Proteins and RNA molecules coalesce into viscous structures that concentrate specific molecules and exclude others. This organization lets cells choreograph complex tasks — transcribing genes, splicing RNA or orchestrating stress responses — with remarkable efficiency and spatial precision.
Yet, probing these structures has proved tricky. Most tools available to researchers either dissolve all condensates indiscriminately or involve manipulations that alter more than the targeted structure, often triggering compensatory changes across the cell.
The killswitch, by contrast, is more surgical. It doesn’t dissolve condensates or prevent them from forming. Instead, it infiltrates and fixes them in place, transforming dynamic blockemblies into static ones.
“You basically just superglue the targeted protein in condensates,” explains Denes Hnisz, a biochemist at the Max Planck Institute of Molecular Genetics in Berlin, who co-led the study.
Stuck in place
Armed with a nanobody-based delivery system, the killswitch can then be steered towards specific condensates in living cells, arresting proteins that once moved freely and revealing how the physical properties of these droplets shape their biochemical roles. “It enables us to really change the emergent properties of condensates,” Hnisz says.
Focusing on the nucleolus — a droplet-like structure involved in producing the cell’s protein-making machinery — Hnisz and his colleagues showed that immobilizing one of its key scaffolding proteins disrupted its internal dynamics and molecular composition, unexpectedly causing some components to be excluded from the structure entirely.
The researchers also applied the killswitch in two disease-specific contexts. In leukaemia cells, targeting condensates formed by cancer-driving protein fusions rapidly reduced the proliferation of malignant cells in mice. In virus-infected cells, directing the killswitch to condensates involved in viral blockembly sharply curtailed the production of infectious particles.
Droplets to drugs
Such findings hint at therapeutic opportunities in the growing field of condensate-targeted drug discovery.
“You can imagine using this rationale to design a cell-penetrating peptide that homes to a specific disease-driving condensate and changes its emergent properties,” says Isaac Klein, chief scientific officer of Dewpoint Therapeutics, a condensate-focused drug company in Boston, Mblockachusetts.
Alternatively, notes Klein, the killswitch could serve as a drug-discovery tool — for example, to identify compounds that alter condensate properties in similar ways. “It sets the stage for it,” he says.
