Programmable Atom‐Like Nanoparticle Reporters for High‐Precision Urinalysis of In Situ Membrane Proteins

Abstract The expression of disease‐specific membrane proteins (MPs) is a crucial indicator for evaluating the onset and progression of diseases. Urinalysis of in situ MPs has the potential for point‐of‐care disease diagnostics, yet remains challenging due to the lack of molecular reporter to transform the expression information of in situ MPs into the measurable urine composition. Herein, a series of tetrahedral DNA frameworks (TDFs) are employed as the cores of programmable atom‐like nanoparticles (PANs) to direct the self‐assembly of PAN reporters with defined ligand valence and spatial distribution. With the rational spatial organization of ligands, the interaction between PAN reporters and MPs exhibits superior stability on cell‐membrane interface under renal tubule‐mimic fluid microenvironment, thus enabling high‐fidelity conversion of MPs expression level into binding events and reverse assessment of in situ MP levels via measurement of the renal clearance efficiency of PAN reporters. Such PAN reporter‐mediated signal transformation mechanism empowers urinalysis of the onset of acute kidney injury at least 6 h earlier than the existing methods with an area under the curve of 100%. This strategy has the potential for urinalysis of a variety of in situ membrane proteins.