A study published in Nature Cell Biology (2024) reveals that a significant portion of the eukaryotic cytoplasm is organized into mesoscale biomolecular condensates (BMCs), which are typically liquid-like and range in size from about 100 nm. Using quantitative proteomics, filtration, and size exclusion experiments, the researchers found that at least 18% of the proteome is organized into such condensates, which are stabilized by RNA or gelation. These condensates are smaller than previously thought and are not easily detectable by conventional microscopy due to the diffraction limit of light. The study also shows that these condensates are more stable upon dilution than expected for those formed through liquid-liquid phase separation (LLPS), suggesting the presence of solid-like cores. RNA-RBP interactions play a major role in the time-dependent squeezing behavior observed in the filtration experiments. The study further demonstrates that more than 15% of all RNAs exhibit behavior consistent with organization via BMCs, with a significant proportion being involved in developmental regulation. The findings suggest that BMCs are widespread in the cytoplasm and may play a crucial role in various cellular functions. The study also highlights the potential of proteomics data to enhance the prediction of LLPS proteins and suggests that these condensates may exist on surprisingly short length scales without coalescing into larger structures. The research provides new insights into the organization of the eukaryotic cytoplasm and the role of BMCs in cellular processes.A study published in Nature Cell Biology (2024) reveals that a significant portion of the eukaryotic cytoplasm is organized into mesoscale biomolecular condensates (BMCs), which are typically liquid-like and range in size from about 100 nm. Using quantitative proteomics, filtration, and size exclusion experiments, the researchers found that at least 18% of the proteome is organized into such condensates, which are stabilized by RNA or gelation. These condensates are smaller than previously thought and are not easily detectable by conventional microscopy due to the diffraction limit of light. The study also shows that these condensates are more stable upon dilution than expected for those formed through liquid-liquid phase separation (LLPS), suggesting the presence of solid-like cores. RNA-RBP interactions play a major role in the time-dependent squeezing behavior observed in the filtration experiments. The study further demonstrates that more than 15% of all RNAs exhibit behavior consistent with organization via BMCs, with a significant proportion being involved in developmental regulation. The findings suggest that BMCs are widespread in the cytoplasm and may play a crucial role in various cellular functions. The study also highlights the potential of proteomics data to enhance the prediction of LLPS proteins and suggests that these condensates may exist on surprisingly short length scales without coalescing into larger structures. The research provides new insights into the organization of the eukaryotic cytoplasm and the role of BMCs in cellular processes.