Inside all cells, there are lipid molecules that make up cell membranes and help organelles communicate and respond to stress. Researchers have struggled to observe the actions of lipids because current detection tools lack sufficient sensitivity and selectivity, hindering progress in understanding lipids.
Now, a team led by Osaka University researchers has developed a way to “evolve” custom biological sensors to track these molecules inside living cells. In a study published this month, natural cell biologyan interdisciplinary team introduced a cell surface liposome binding (CLiB) assay. This is a high-throughput method that uses yeast cells, liposomes (microscopic capsules made of lipids), and fluorescence readouts to test how thousands of protein variants bind to lipids.
Until now, researchers have lacked a systematic way to develop specific lipid biosensors, which has been a major bottleneck in studying the role of lipids in biology and disease. However, this new high-throughput technology, the CLiB assay, allows us to test vast numbers of proteins at once and quickly find the best match. ”
Taki Nishimura, first author
Using the CLiB assay, the team screened a library of protein variants, improved existing sensors through an evolution-like process, and created a new probe called PX-SnxAGV. This probe can detect the rare signaling lipid PI(3,5)P2. PI(3,5)P2 is notoriously difficult to trace as it is usually present in trace amounts.
In living cells, this probe revealed a surprising pattern. Under stress conditions, such as a sudden increase in salt, PI(3,5)P2 accumulates in small distinct regions of the membrane. Similarly, in mammalian cells undergoing microautophagy, a “self-eating” purification process in which the cell’s recycling centers, lysosomes, directly take up and degrade damaged components, PI(3,5)P2 becomes concentrated at sites where membranes fold inward and begin to engulf cargo.
Beyond these findings, the new CLiB technique may have a wide range of applications. Many diseases involve problems with cell membranes, so a deeper understanding of lipids may open new avenues for treatment.
“With these probes, we can now learn when and where lipids appear in cells,” Nishimura explains. “These advances will improve our understanding of the membrane lipid environment and how it influences a wide range of diseases, including cancer, diabetes, and neurodegenerative diseases.”
By detecting previously invisible molecules, the CLiB assay provides a new way to study the inner workings of cells and has the potential to accelerate discoveries across cell biology, medical research, and AI-driven drug discovery.
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Reference magazines:
Tetsuya Nishimura Others. (2026) Cell surface liposome conjugation (CLiB) enables lipid-bound probe engineering via high-throughput screening. natural cell biology. DOI: 10.1038/s41556-026-01996-8. https://www.nature.com/articles/s41556-026-01996-8
