Real‐time biosensing of Parkinson's disease biomarkers via NIR‐activated upconversion nanoparticles

Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder with incompletely understood pathophysiology, necessitating advanced tools for long‐term dynamic biomarker monitoring. Current techniques lack noninvasive platforms capable of real‐time multiparametric monitoring with high stability, sensitivity, and responsiveness. Here, we engineered core‐shell‐shell lanthanide‐doped upconversion nanoparticles (cssUCNPs) through controlled Tm 3+ /Er 3+ gradient doping and crystal field symmetry modulation. This “sandwich” heterostructure design suppressed cross‐relaxation, while Ca 2+ doping enhanced radiative transition efficiency. These modifications yielded a quantum yield improvement from 0.35 ± 0.014% to 3.27 ± 0.067%, representing a 9.3‐fold enhancement, alongside a fluorescence intensity increase of 425.5‐fold. The cssUCNPs exhibited exceptional photostability (>10,000 excitation cycles) and biocompatibility (>95% cell viability). Upon integration of Fluo4 with UCNPs, the system harnessed the luminescence resonance energy transfer effect to enable dual‐responsive sensing of Ca 2+ (detection limit: 1 μM) and temperature (sensitivity: 0.5 K −1 ), thereby facilitating long‐term tracing of Ca 2+ and temperature dynamics across PD pathological stages. Our results revealed that early‐phase PD is characterized by rapid Ca 2+ and temperature surges, followed by oscillatory fluctuations in the middle phase, and eventual stabilization at elevated levels in the terminal phase. These dynamic profiles establish a direct link between mitochondrial dysfunction and Ca 2+ dysregulation, highlighting Ca 2+ flow‐sensitive and thermally sensitive therapeutic targets for PD intervention.