Triethylamine-mediated protonation–deprotonation unlocks dual-drug self assembly to suppress breast cancer progression and metastasis

• DOI: 10.1073/pnas.2416796122
• Publication Date: 2025-01-28T18:40:11Z
• Authors: Lei Lei; Yujun Song; Lianyi Yang; Yazhen Wang; Xue Xia; Yiwei Zhang; Xiaoxian Zhang; Xuequan Zhang; Ishaan Duggal; Bin He; Nicholas A. Peppas; Jun Cao; Huile Gao

Carrier-free nanomedicines exhibited significant potential in elevating drug efficacy and safety for tumor management, yet their self assembly typically relied on chemical modifications of drugs or the incorporation surfactants, thereby compromising drug’s inherent pharmacological activity. To address this challenge, we proposed a triethylamine (TEA)-mediated protonation–deprotonation strategy that enabled adjustable-proportion dual without modification, achieving nearly 100% loading capacity. Molecular dynamic simulations, supported by experiment evidence, elucidated underlying self-assembly mechanism. Specifically, TEA facilitated deprotonation Doxorubicin (Dox) α-Tocopherol succinate (α-tos), causing Dox to transition from hydrophilic hydrophobic state, while simultaneously increasing hydrophilicity α-tos. This allowed fine-tuned balance between properties two compounds, enabling precise into carrier-free nanomedicine (DT) with tailored ratio. The engineered DT demonstrated ability accumulate at sites release its therapeutic controlled manner. combination α-tos synergistically generated reactive oxygen species modulated expression matrix metalloproteinase-9, leading superior antitumor metastasis, maintaining excellent profiles. Our findings provided unique perspectives design cancer therapy, laying solid foundation clinical translation.