Self-Assembling Imidazolium Nanoaggregates Trigger a Unique Dynamin-Dependent Cell Death via Cytoplasmic Vacuolization and Mitochondrial Dysfunction in Human Lung Adenocarcinoma

The identification of alternative cell death pathways is key to developing therapies for apoptosis-resistant cancers. We investigated cell death induced by delocalized lipophilic cation (DLC) nanoaggregates in A549 lung carcinoma cells. These DLCs trigger a dynamin-dependent, nonapoptotic pathway involving cytoplasmic vesicle accumulation and mitochondrial dysfunction. Leveraging the mitochondria-targeting ability of lipophilic cations, we designed and synthesized fluorescent mitochondrion-toxic molecules with potent cytotoxicity against A549, MDA-MB-231, and MCF-7 cells. Dynamic light scattering revealed the nanoaggregate formation of the lead compound, L3, in the RPMI media. L3 inhibited metastasis and clonal expansion, induced vacuole formation post endocytosis, and impaired the mitochondrial function, disrupting ATP levels. This led to mitochondrial permeability transition pore (MPTP) opening and oxidative imbalance via glutathione perturbation. L3 demonstrated strong antitumor activity in vitro and in vivo, showing high potential for treating apoptosis-resistant cancers.