Evolution of Multivalent Aptamer Corona for High‐Throughput Multiplexed Detection of Multiple Cancers

Abstract Clinical in vitro diagnosis is essential in early diagnosis and prognostic assessment, yet antibody‐based assays face limitations in multiplexity and scalability. To address the growing demand for modern molecular diagnostics, a multivalent aptamer corona platform for high‐throughput is introduced and multiplexed multi‐cancer diagnosis. With clinical serum samples, ovarian cancer‐, lung cancer‐, and colorectal cancer‐based aptamer coronas are obtained through several rounds of alternating positive and negative systematic evolution of ligands by exponential enrichment (SELEX). Leveraging a de novo ProteoFish‐SELEX strategy, which integrates nanoparticle‐protein corona technology, a multivalent aptamer corona is evolved. Proteomic profiling of protein coronas revealed cancer‐associated protein signatures, while aptomic profiling of aptamer coronas identified high‐affinity cancer‐specific aptamers. With these aptamers, high diagnostic accuracy is demonstrated in multiplexed multi‐cancer detection using clinical cohorts. Multivalent aptamer corona's outstanding diagnostic performance, multiplexed detection capability, and sequencing‐enabled high‐throughput potential position it as a promising versatile tool for novel biomarker discovery and a transformative advancement in precision oncology.