Label-free quantitative nanoscopy for molecular specific identification at depth in pristine living biological tissues

ongoing

Optical microscopy has undergone a revolution that now allows us to access molecular resolution (“nanoscopy”) with the identification of specific biomolecules within biological samples. Nanoscopy has become a key approach to decipher the function of living matter since biomolecules are the elementary building blocks. While being a major tool, high-resolution and specificity can only be achieved by tagging the molecules of interest with fluorescent probes, which inevitably alters the samples, making them improper for medical applications including regenerative medicine. The leading dogmas being that (i) nanoscopy cannot be achieved without labelling and (ii) no specific signature from molecules can be retrieved without energy exchange with the sample (e.g. absorption by probes, molecular vibrational interaction). I propose a complete change of paradigm by introducing label-free nanoscopic imaging using the optical refractive index as a molecular sensor. My ground-breaking approach will be based on our pioneering work which demonstrates that phase, intensity and polarisation information can be quantitatively retrieved with unprecedented sensitivity and with an imaging resolution equivalent to regular imaging with fluorescent probes. I will re-forge this into a single-shot imaging technique capable of beating the optical resolution limit to access nanoscale resolutions, even deep inside living unmodified biological samples. Specific molecular information will be untangled through machine learning algorithms. SPECIPHIC will give birth to the first label-free molecular specific imaging with nanoscale resolution in pristine living biological tissues. The applicability of my concept will be demonstrated in this ERC starting project with applications in regenerative medicine and oncology, impacting thus directly important societal questions. My new approach will impact many other fields, in the biomedical world first but also in physics and for nanomaterial engineering.