Chemically Resolving Protein Phase Separation with Quantum-Enhanced Picoliter NMR

摘要

Biomolecular condensates formed through liquid–liquid phase separation (LLPS) organize essential cellular functions as membraneless organelles. Understanding their internal atomic-level chemistry is critical, but inaccessible to classical nuclear magnetic resonance (NMR) due to their picoliter volumes. While emerging quantum sensing has extended NMR to this scale, applying this capability to chemically resolve biologically significant microenvironments remains a key objective. Here, we introduce a diamond nitrogen-vacancy quantum sensor with a 0.19 ppm resolution in ~12 pL. Enabled by confined-chamber deuteration, protective metallization, and sensitivity enhancement, this platform enabled chemically resolved protein NMR spectra of LLPS condensates, distinguishing protons in distinct structural positions. This work extends atomic-resolution spectroscopy to the subcellular scale, opening a window onto the molecular environments that underlie heterogeneous function at the cell scale.