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.