Lysosome-targeting naphthalimide-based AIEE nanoaggregates as a dual inducer of autophagy and apoptosis in cancer therapy.

Hallmarks of cancer remain incompletely addressed due to the lack of efficient treatments. In translational healthcare, aggregation-induced emission/aggregation-induced enhanced emission luminogens (AIE/AIEEgens), which display strong photoluminescence upon aggregation, have broad applications in therapeutic imaging, selective organelle tracking, and biomolecular detection. Carefully designed AIE/AIEEgens can generate intracellular reactive oxygen species (ROS), thereby activating apoptotic pathways. Here, we report a novel naphthalimide-based fluorophore functionalized with morpholine and 6-hydroxyquinoline units. DFT studies confirmed a donor-acceptor framework, with morpholine as the electron donor and the naphthalimide core as the electron acceptor. The synthesized AIEEgen morpholinonaphthalimide-6-hydroxyquinoline (M6HQ) efficiently targeted lysosomes and exhibited cytotoxicity in IMR-32 and MCF-7 cells. M6HQ enhanced lysosomal activity that instigated increased LC3-II/LC3-I expression and decreased p62 expression, indicating autophagic induction. Additionally, M6HQ elevated intracellular ROS production, leading to mitochondrial depolarization, cell cycle arrest, reduced cell migration, and apoptosis in IMR-32 and MCF-7 cells. Elevated levels of apoptotic marker proteins (cleaved caspase-3 and -9) in treated cells further supported the apoptotic cell death pathway. These findings highlight lysosome-targeted naphthalimide-based AIEE nanoaggregates as multifunctional theranostic agents that induce both autophagy and apoptosis, offering a dual-pathway strategy to overcome drug resistance and improve cancer therapy.