Applications and prospects of cryo-electron tomography in drug discovery and understanding disease.

Cryo-electron tomography (cryo-ET) is emerging as a transformative tool for structural biology. Unlike methods based on purified molecules, cryo-ET enables visualisation of macromolecules directly within intact cells and tissues, preserving their native interactions and physiological context. By providing high-resolution views of healthy and diseased cells, cryo-ET offers a powerful means to understand infection and disease mechanisms. Moreover, cryo-ET combined with subtomogram averaging can resolve macromolecular structures beyond 3 Å resolution, making it a promising approach for computational drug discovery. This article highlights the recent contributions from cryo-ET in understanding human disease and examines future perspectives of this rapidly evolving technique in structure-based drug discovery. We propose a roadmap for the developments required for its widespread adoption in pharmacological research.