Nowadays, gastroesophageal reflux disease (GERD) has emerged as one of the major hazards to the health of the upper gastrointestinal tract, and there is an urgent need for a low-cost, user-friendly, and non-invasive detection method. Herein, a paper-based sensor (CP sensor) for the non-invasive screening of GERD is proposed. The sensor is structured as a specially shaped cellulose paper strip embedded with fluorescent colloids, which are self-assembled from a cleavable synthetic fluorescent polymer (P4). Benefiting from the introduction of amide bonds and the unique assembled structure of the nanocolloids, the pepsin in the sample solution will hydrolyze the water-soluble branches in the micellar shell during detection, resulting in a corresponding output of the fluorescent signal. This responsiveness, which can be observed by the naked eye, is so sensitive with a minimum detectable concentration for pepsin as low as 0.3 ng·mL