PD-L1 targeting in triple negative breast cancer: in silico and in vitro validation of wasp venom peptide MP-1.

Triple-negative breast cancer is an aggressive cancer with high metastatic potential and limited treatment options. The current study investigated the anticancer activity of the Polybia-derived MP-1 peptide, formulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles, for inhibiting PD-L1 and epithelial mesenchymal transition (EMT)-associated signalling in triple-negative breast cancer (TNBC). Computational screening of molecules identified MP-1 as a stable high-affinity binder of PD-L1 possessing high anticancer prediction scores. The MP-1-PLGA nanoparticles that were optimized showed the spherical structures with a size of 104.4 nm as well as a PDI of 0.231. Moreover, their encapsulation efficiency was 71.5%. The formulation showed a controlled release with 41.65% over 72 h (p < 0.01). According to in vitro assays, the lower IC₅₀ value of MP-1-PLGA nanoparticles (19.39 µg/mL) than free MP-1 (53.51 µg/mL) confirmed enhanced cytotoxic activity. Gene expression studies showed significant down regulation of PD-L1, EGFR, STAT3, BCL2 and Ki-67, while the up regulation of Caspase-3, Caspase-9 and BAX (p < 0.0001). Western blot results verified reduced expression of PD-L1 and EGFR. The PLGA nanoparticles loaded with MP-1 targeted the PD-L1 effectively and modulated the Molecular Pathways related with EMT which inhibit tumor cell proliferation and enhance their apoptosis. The results indicate MP-1-PLGA as a potential nontherapeutic candidate for improving TNBC treatment.