Self-assembly of paclitaxel and cyclosporine A to overcome tumor drug resistance.

The clinical application of paclitaxel (PTX) is frequently hindered by multidrug resistance driven by the overexpression of P-glycoprotein (P‑gp). To cooperatively overcome the challenges of drug efflux and tumor resistance, we designed a Zn2+‑coordinated supramolecular self‑assembly strategy, successfully integrating PTX with the P‑gp inhibitor cyclosporine A (CsA) into novel paclitaxel‑based nanorods (PTXNDs‑CsA). The coordinated Zn2+ acts as a structural scaffold to enhance the stability of PTXNDs‑CsA, while also enabling precise pH‑responsive drug release within the acidic tumor microenvironment. Moreover, PTXNDs‑CsA effectively promoted drug uptake in drug‑resistant tumor cells (MDA‑MB‑231/Taxol) and significantly enhanced the rate of tumor cell apoptosis. In the subcutaneous drug‑resistant breast cancer xenograft model, PTXNDs‑CsA exhibited superior tumor‑suppressive efficacy compared to PTX monomer and single‑component nanorods (PTXNDs), without inducing noticeable systemic toxicity or organ damage. By integrating Zn2+ coordination with drug‑resistance reversal mechanisms, this study successfully established an efficient, stable, and intelligently responsive co‑delivery nanoplatform, offering not only a novel strategy to overcome clinical PTX resistance but also a promising platform for developing synergistic therapeutic approaches against multidrug‑resistant tumors.