Supramolecular Probe for Monitoring Lysosomal Ferritinophagy to Facilitate the Early Diagnosis of Parkinson's Disease

ABSTRACT Lysosomal iron overload, resulting from dysregulated ferritinophagy, is a significant early event in the progression of Parkinson's disease (PD). This condition causes iron accumulation within cells, triggering oxidative stress and ferroptosis, along with mitochondrial dysfunction and α‐synuclein (α‐syn) aggregation, ultimately damaging dopaminergic neurons irreversibly. However, tools for real‐time monitoring of Fe 3+ dynamics in vivo are limited. In this study, we introduce TPE‐4B/4Q[7], a supramolecular fluorescent probe designed for selective and stable tracking of Fe 3+ changes within lysosomes. This probe exhibits excellent photostability, low cytotoxicity, and a detection limit of 1.23 × 10⁻⁶ M. In cellular models of PD, TPE‐4B/4Q[7] effectively monitors lysosomal ferritinophagy‐induced Fe 3+ overload, allowing for the assessment of oxidative stress, mitochondrial function, and the levels of key biomarkers such as α‐syn and tyrosine hydroxylase. Additionally, this probe can track iron accumulation linked to neurodegenerative lesions in Caenorhabditis elegans and MPTP‐induced PD mouse models, with signal changes correlating closely with neurodegenerative phenotypes and molecular pathology. Notably, TPE‐4B/4Q[7] enables non‐invasive brain imaging via nasal delivery. TPE‐4B/4Q[7] is a sensitive molecular indicator for early risk assessment and monitoring of PD progression. It is anticipated to be an effective instrument for the early diagnosis of PD.