Aggressive triple-negative breast cancer (TNBC) is a current threat worldwide. The ineffectiveness of current TNBC therapy options highlights the need for innovative therapeutics. Due to bioavailability issues and probable side effects, parthenolide (PTL), the potent anticancer bioactive component of Tanacetum parthenium, has restricted therapeutic applicability. To address these challenges, a pH-responsive nanodelivery system containing PTL (cross-linked nanocarrier endowed with poly-β-thioester activity carrying PTL (CBAPTL)) was developed. In order to facilitate sustained release of PTL at endosomal-like pH (5.0−5.3) in cancer cells, the pH-responsive CBAPTL was synthesized. The effectiveness of CBAPTL was examined in vitro using human TNBC cells (MDA-MB-231) through Western blotting, flow cytometry, invasion assay, and mammosphere inhibition study and compared its effect on WRL-68 normal cells. In MDA-MB-231 cells, CBAPTL exhibited selective cytotoxicity and arrested the cell cycle at the G2-M phase more effectively than PTL. CBAPTL induced apoptosis via downregulating Bcl-2 and upregulating p53, BAD, and p21. It showed antimetastatic efficacy by inhibiting AKT-phosphorylation, p38, and MMP1 expression. CBAPTL caused Δψm disruption and hindered cell migration, invasion, and EMT by suppressing vimentin, Snail, CD44, and mammosphere development, demonstrating its effect against metastasis and cancer stem cells (CSCs). Contrarily, CBAPTL showed no effect on WRL-68 normal cells. CBAPTL selectively delivered PTL at the TME, facilitating enhanced internalization through endocytosis in MDA-MB-231 cells. The findings highlight the superior and selective efficacy of CBAPTL compared to PTL against TNBC cells, indicating a potential therapeutic strategy for managing cancer aggressiveness without impacting normal cells.
