Biomimetic fluidic lipid-engineered nanofluidic platform for ultrasensitive discrimination of multiprotein in biofluids.

Accurate multiprotein discrimination in complex biofluids remains challenging due to static recognition interfaces, severe biofouling, and ambiguous size-exclusion effects in conventional solid-state sensors. Herein, we develop a fluidic lipid-based antifouling and rectification-engineered (FLARE) system, a dynamic nanofluidic platform that enables electrochemical fingerprint-based multiprotein discrimination. Constructed via in situ self-assembly of a biomimetic lipid membrane on nanochannel arrays, FLARE establishes a covalently stabilized yet laterally fluid and programmable interface, enabling adaptive target recognition while minimizing nonspecific adsorption. Upon protein binding, target-dependent interfacial charge perturbations arising from distinct isoelectric properties are nonlinearly amplified via ion current rectification (ICR), generating characteristic voltage-dependent electrochemical fingerprints. This ICR-governed signal encoding mechanism converts subtle molecular differences into high-dimensional readouts, enabling intrinsic discrimination beyond conventional intensity-based sensing. By integrating sensitive capture with encoded signal transduction, FLARE achieves ultrasensitive detection of protein biomarkers, with detection limits of 0.192 pM (TNF-α), 1.51 pM (lysozyme), 2.44 pM (APE1), and 3.39 pM (IL-1β). Coupled with principal component analysis, FLARE enables accurate discrimination of six proteins spiked in whole blood. This work establishes a dynamic and chemically adaptable nanofluidic interface for multiplexed protein analysis in complex biological matrices, demonstrating strong potential for clinical diagnostics.