SPECTRAL: An Intelligent and Ultra‐Sensitive Photonic Hydrogel Platform for Biomarker‐Based Cancer Prediction

Point-of-care (POC) biosensing holds great promise for noninvasive cancer diagnostics, as circulating tumor DNA (ctDNA) serves as a minimally invasive biomarker for early detection. However, effective ctDNA detection remains challenging due to low abundance and complex workflows. Herein, we present SPECTRAL (Smart Photonic-hydrogel Enhanced chip for Cancer Type Recognition and AnaLysis), a sequencing-free platform integrating photonic-crystal hydrogels with charge-neutral peptide nucleic acid (PNA) probes for efficient volumetric signal transduction and single-nucleotide discrimination. Photonic-crystal-enhanced fluorescence amplifies signals of fluorescently labeled recombinase polymerase amplification (RPA) amplicons, achieving a detection limit of 100 copies per µL, with substantially improved sensitivity over conventional fluorescence assays. A single SPECTRAL chip simultaneously profiles 205 ctDNA mutations and eight protein biomarkers from plasma samples. The PNA sensor library is generated via an automated synthesis system guided by machine learning (ML)-predicted probe difficulty. Multimodal signals are analyzed using cloud-based ML to classify multiple cancer types (lung, breast, and colorectal), achieving 90.0% specificity and 86.7% sensitivity (87.5% overall accuracy) within 100 min from sample to diagnosis, based on validation with patient plasma samples. By combining molecular biosensing, photonic signal amplification, and AI-driven analysis, SPECTRAL provides a low-instrument-dependent platform for decentralized liquid-biopsy cancer diagnostics.