Interpretable Machine Learning-Aided Optical Deciphering of Serum Exosomes for Early Detection, Staging, and Subtyping of Lung Cancer

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, underscoring an urgent need for strategies that enable early detection and phenotypic classification. Here, we conducted a label-free surface-enhanced Raman spectroscopic (SERS) analysis of serum exosomes from 643 participants to elucidate the biochemical deregulation associated with LC progression and the unique phenotypes of different LC subtypes. Iodide-modified silver nanofilms were prepared to rapidly acquire SERS spectra with a high signal-to-noise ratio using 0.5 μL of patient exosomes. We performed interpretable and automated machine learning (ML) analysis of differential SERS features of serum exosomes to build LC diagnostic models, which achieved accuracies of 100% and 81% for stage I lung adenocarcinoma and its preneoplasia, respectively. In addition, the ML-derived exosomal SERS models effectively recognized different LC subtypes and disease stages to guide precision treatment. Our findings demonstrate that spectral fingerprinting of circulating exosomes holds promise for decoding the clinical status of LC, thus aiding in improving the clinical management of patients.