A supramolecular fluorescent probe targeting mitochondrial iron for assisting early Parkinson's disease diagnosis.

Abstract

Early detection of Parkinson's disease (PD) before irreversible dopaminergic neuron loss remains a critical unmet need. Herein a novel supramolecular probe, DTPP@Q[7], was constructed via a host-guest assembly in which the fluorescent molecule DTPP is combined with the macrocycle cucurbit[7]uril (Q[7]) for real-time monitoring mitochondrial iron overload, an early pathological driver of PD. Encapsulation of DTPP fluorophore by Q[7] exposes the TPP targeting group, enabling precise mitochondrial localization (Pearson coefficient 0.95 with Mito-Tracker) while imparting higher photostability. The probe exhibits high selectivity and sensitivity for Fe³⁺, with a detection limit of 0.36 μM. Fluorescence quenching induced by mitochondrial Fe³⁺ correlates with ferroptosis markers (ROS, GPX4, LPO, and MDA) in PD cells and tracks mitochondrial dysfunction, pathological α-synuclein aggregation, and altered dopamine synthesis, demonstrating dynamic reporting of neurodegenerative progression. In an MPTP mouse model, intranasal DTPP@Q[7] enables noninvasive monitoring of cerebral iron imbalance: probe fluorescence decreases dose-dependently and correlates with substantia nigra iron accumulation (R² > 0.99). In the high-dose MPTP group fluorescence fell by 76%, α-synuclein is upregulated ∼2.5-fold, and tyrosine hydroxylase expression drops nearly 40%. By capturing molecular pathology prior to neuronal morphological damage, DTPP@Q[7] offers a promising molecular strategy for early PD diagnosis.