NPY-functionalized niosomes for targeted delivery of margatoxin in breast cancer therapy.

Neuropeptide Y (NPY) and the voltage-gated potassium channel Kv1.3 are closely associated with breast cancer progression and apoptosis regulation, respectively. NPY receptors (NPYRs), which are overexpressed in breast tumors, contribute to tumor growth, migration, and angiogenesis. In parallel, Kv1.3 plays a pivotal role in mitochondrial-mediated apoptosis, and its inhibition can induce cancer cell death. To exploit these mechanisms, we developed and characterized a novel niosomal drug delivery system encapsulating margatoxin (MgTx), a potent Kv1.3 inhibitor, and functionalized with NPY for targeted breast cancer therapy. Niosomes were synthesized via a modified thin-film hydration method and decorated with NPY peptides to enable selective binding to NPYR-overexpressing cancer cells. Physicochemical analyses using dynamic light scattering (DLS), atomic force microscopy (AFM), and field emission scanning electron microscopy (FESEM) confirmed a nanoscale size range (134-161 nm), spherical morphology, and successful surface modification. The system demonstrated high encapsulation efficiency, prolonged stability at 4°C, and sustained MgTx release over 72 h. In vitro cytotoxicity studies revealed that NPY-decorated MgTx-loaded niosomes significantly reduced the viability of MCF-7 and MDA-MB-231 breast cancer cells while exerting minimal toxicity on non-tumorigenic MCF-10A cells. qRT-PCR analysis indicated upregulation of pro-apoptotic genes (Bax, Caspase-3) and downregulation of anti-apoptotic Bcl2, confirming induction of apoptosis in treated cancer cells. These findings highlight the potential of NPY-functionalized niosomes as an effective and selective nanoplatform for targeted breast cancer therapy.