Dual-drug loaded hyaluronic acid conjugates coated polydopamine nanodrugs for synergistic chemo-photothermal therapy in triple negative breast cancer

Although combination of chemotherapy and photothermal therapy (PTT) holds significant promise for treating triple-negative breast cancer, the existing delivery systems for achieving synergistic antitumor activity remains unsatisfactory. Herein, we developed of dual-drug loaded hyaluronic acid (HA) nanodrugs, which exhibited pH, glutathione (GSH), and thermal triple-responsiveness and CD44-targeting capabilities for chemo-PTT synergistic therapy in breast cancer. Gemcitabine (GCB) and metformin (MET) were conjugated to HA via amide and disulfide bonds to form dual-drug loaded prodrugs (HSGM), which were then coated onto the surface of polydopamine nanoparticles (PDA NPs) to self-assemble into HSGM/PDA NPs. These NPs selectively accumulated at the tumor site through HA receptors and released GCB and MET in response to low pH and high GSH concentrations. The NPs demonstrated excellent photothermal performance, with heat generated from near-infrared (NIR)-laser irradiation accelerating drug release within tumor. Additionally, MET inhibited the production of heat shock protein 70 (HSP 70), mitigating thermotolerance induced by PTT, thereby enhancing the PTT effect. The combination of chemotherapy and PTT synergistically improved anti-tumor efficacy (tumor inhibition ratio: 99.11 %) while showing negligible systemic toxicity, effectively preventing tumor metastasis and recurrence. This integrated approach offers valuable insights for the clinical treatment of breast cancer and other malignant tumors.