Ballistic Microscopy Achieves Spatially Resolved Molecular Sampling of Live Cells at 1,000 m/s

A groundbreaking new imaging technique, dubbed Ballistic Microscopy (BaM), is enabling scientists to extract and analyze molecular information from live cells with unprecedented spatial resolution. The method, detailed in a recent preprint by A.S.J. and M.P., involves bombarding living cells with millions of nanoparticles traveling at approximately 1,000 meters per second, effectively creating a "physical image" of the cell's internal components. This innovative approach promises to revolutionize the study of cellular architecture and function by decoupling sample capture from detection.

The core concept behind BaM challenges traditional microscopy, which relies on photons or electrons to visualize matter. As stated in the paper, "Light and electron microscopy utilizes interactions of either photons or electrons with matter to create images," implying that "we see small objects by literally hurling things at them," as noted by Niko McCarty in a recent social media post. BaM extends this principle by using physical nanoparticles, or "nano-bullets," to penetrate cells, collect cytoplasm, and deposit it onto a hydrogel film, preserving the spatial organization of the collected material.

Each nano-bullet, ranging from 50 to 1,000 nanometers in diameter, pierces the cell, picks up attoliters of cytoplasm, and embeds itself in a hydrogel film placed beneath the sample. This process allows for the subsequent analysis of the collected molecules, such as proteins and metabolites, using techniques like mass spectrometry or cryo-electron microscopy. The precise trajectory of the nano-bullets ensures that their position in the hydrogel directly correlates with their path through the cell, providing both spatial and molecular information without the need for labels.

The researchers demonstrated BaM's utility by discovering Keratin-18 as a structural element within CLIP170 and Tau3R condensates in HEK cells, highlighting the technique's capacity for de novo discovery of unknown biomolecules. This label-free method offers significant advantages over conventional techniques that are often limited to predefined targets or lack subcellular spatial resolution. The technology is covered by a published US patent (WO/2024/044276) assigned to M.P. and A.S.J., underscoring its novelty and potential impact.

While currently a proof-of-concept, BaM shares a creative problem-solving spirit with Expansion Microscopy, another innovative technique that physically enlarges biospecimens to overcome resolution limits. The authors anticipate similar advancements in BaM's resolution, potentially through the use of smaller nanoparticles, though this presents trade-offs in penetration and trajectory stability. The development of BaM marks a significant step towards understanding the complex molecular landscape of living cells in their native state.