The research group of Prof. Apurba Lal Koner, Department of Chemistry developed a series of morpholine-anchored fluorescent probes, designated as SC-nmor (n = 2, 4, 6), for the visualization of protein aggregates. These probes exhibit pronounced photophysical changes upon interaction with protein fibrils, attributed to their high sensitivity to the fibrillar microenvironment. Among different probes, SC-4mor stands out for its strong selectivity toward aggregated insulin over native insulin, accompanied by a notable enhancement in fluorescence lifetime. Live-cell imaging confirms the exclusive localization of SC-4mor within the lysosomal compartment, enabling clear visualization of lysosome-accumulated protein fibrils, particularly those induced by pepstatin A treatment. In vivo studies using genetically mutated and high-sugar diet-modified Drosophila melanogaster representing both neurodegenerative and non-neurodegenerative models further demonstrate the probe’s capacity to stain protein aggregates. Notably, enhanced emission from the eye lobes of A?-mutated and HSD brain samples indicates that SC-4mor can exhibit adequate retention in the brain with minimal biological toxicity. Importantly, SC-4mor also exhibits the ability to cross the blood-brain barrier in a mouse model. These features position SC-4mor as a promising fluorogenic marker for detecting and monitoring neurotoxic protein fibrillation in live cells and animal models, providing valuable insights into the mechanisms underlying protein aggregation and neurodegeneration. For more details, kindly visit https://onlinelibrary.wiley.com/doi/10.1002/smll.202570164?af=R
