Timely detection of early atherosclerosis (AS) is crucial for improving cardiovascular outcomes, creating a growing demand for diagnostic tools that are simple, sensitive, and cost-effective. Here, we introduce a synthetic nanosensor for early AS detection that leverages the fluorescence and renal clearance properties of carbon quantum dots (CQDs). This nanosensor, designed to respond to the proteolytic activity of AS-associated dysregulated enzymes, entails CQDs as signal reporters to convert AS-associated proteolytic activity to fluorometric readings enabling a sensitive and cost-effective urine-based assay for early AS detection. Our findings demonstrated that the nanosensor provided distinct signals in atherosclerotic versus healthy mice at early AS stages, indicating its diagnostic potential. Moreover, toxicity tests showed no notable adverse effects, supporting its safety for diagnostic applications. This minimally invasive diagnostic approach could facilitate personalized therapy design and continuous efficacy assessment. It is expected that such a modular nanosensor platform can be integrated with simple urine tests to offer cost-effective detection of various diseases.