Perioperative neurocognitive disorders (PND) represent a prevalent and clinically challenging complication following surgery and anesthesia. However, reliable peripheral biomarkers capable of reflecting molecular dysfunction in complex biofluids remain scarce. Dysregulation of the ubiquitin-proteasome system has been increasingly implicated in perioperative neuroinflammation and synaptic dysfunction. Herein, we develop a homogeneous dual-emission ratiometric fluorescent platform based on compositionally correlated perovskite quantum dots (PQDs) for robust profiling of Pan-deubiquitinating enzyme (pan-DUB) activity in perioperative blood samples. Specifically, green-emissive CsPbBr3 PQDs were engineered as the enzyme-responsive channel, while orange-emissive CsPbBr1.5I1.5 PQDs served as an internal reference. Notably, both CsPbBr3 and CsPbBr1.5I1.5 PQDs shared a unified lattice framework and surface chemistry through conformal SiO2 encapsulation, enabling intrinsically matched photophysical responses to different environmental perturbations. By coupling a ubiquitin-derived peptide, pan-DUB-mediated cleavage induced a ratiometric fluorescence increase without perturbing the reference signal, achieving high sensitivity within the range of 0.01–0.5 IU/mL. The limit of detection was calculated to be 0.004 IU/mL. Finally, as-prepared PQD-based sensing platform with high sensitivity and excellent anti-interference was employed to determine the pan-DUB activity in mouse serum of PND. A significant elevation of serum pan-DUB activity following surgery was clearly observed, which strongly correlated with deficits in spatial working memory. Moreover, receiver operating characteristic analysis demonstrated the high discriminative power for distinguishing PND from sham-operated animals (AUC = 1.00). This work established a homogeneous multicolor ratiometric sensing strategy that enabled accurate functional profiling of pan-DUB activity in complex biofluids, offering mechanistic insight and a promising peripheral biomarker approach for perioperative neurocognitive disorders.



