Chitosan NPs delivery of Ailanthus excelsa Roxb. quassinoids suppresses STAT3-driven immune evasion by inhibiting PD-L1 transcription in triple-negative breast cancer

Through STAT3-mediated elevation of PD-L1, triple-negative breast cancer (TNBC), an aggressive subtype with few therapeutic options, often avoids immune surveillance. Ailanthus excelsa quassinoids’ low solubility and bioavailability limit their medicinal potential. The rationale for this study was based on the need to overcome the limited delivery of plant-derived quassinoids while simultaneously targeting STAT3/PD-L1-mediated immune evasion in triple-negative breast cancer (TNBC ). The novelty of this work lies in integrating Ailanthus excelsa quassinoids with chitosan nanoparticle delivery to enhance intracellular bioavailability and directly investigate suppression of STAT3-dependent PD-L1 transcription, apoptosis, and restoration of CD8⁺ T-cell antitumor activity. This approach provides a mechanistically defined phytochemical nanotherapeutic strategy for TNBC. Here, we studied quassinoid delivery (AEQ-CS-NPs) via chitosan nanoparticles in TNBC models. With a mean size of 168.4 ± 12.6 nm, a polydispersity index of 0.23 ± 0.04, a zeta potential of + 31.7 ± 3.2 mV, and an encapsulation efficiency of 82.6 ± 4.8%, the nanoparticles demonstrated improved cellular uptake in MDA-MB-231 and BT-549 cells. PD-L1 mRNA and protein levels were lowered because of AEQ-CS-NP treatment’s considerable suppression of STAT3 phosphorylation. Cytotoxic activity was restored through functional co-cultivation with CD8⁺ T cells. Without changing body weight or serum liver and kidney indicators, AEQ-CS-NPs decreased PD-L1 expression, enhanced CD8⁺ T cell infiltration, and reduced tumor growth by 61% in vivo. All of these results show that A. excelsa quassinoids delivered via nanoparticles efficiently suppress STAT3-driven PD-L1-mediated immune evasion and boost antitumor immunity. The translational potential of AEQ-CS-NPs as a phytochemical-based immunomodulatory strategy for TNBC is highlighted in this study.