Personalized Cancer-Specific Protein-Aptamer Corona for Orthogonal Multiplex Cancer Diagnosis

Aptamers are powerful synthetic recognition elements for biosensing, yet their application in complex biofluids, such as human serum, is critically limited by enzymatic degradation. To overcome this fundamental challenge, we introduce a novel analytical platform centered on the concept of a personalized protein-aptamer corona (PAC). This strategy leverages the spontaneous formation of a disease-specific protein corona on magnetic nanoparticles, which not only enriches low-abundance biomarkers but also creates a stabilized, nuclease-free nanobio interface for subsequent aptamer recognition. The integration of this PAC concept with an 8-channel orthogonal multiplexed electrochemical (OMEC) chip enables sensitive, amplification-free (PCR-free) signal transduction via alternating current voltammetry. By coupling this platform with machine learning algorithms, we translate complex, multiplexed aptamer binding signatures into a robust diagnostic output. Clinical validation on two independent cancer cohorts demonstrated outstanding performance, achieving an area under the curve of 99.50% for ovarian cancer (<i>n</i> = 121) and 96.54% for non-small cell lung cancer (<i>n</i> = 107). This work establishes the PAC-OMEC platform as a versatile and powerful strategy for high-throughput clinical diagnostics, fundamentally addressing the instability of aptamers in native biological samples.