Tumor Microenvironment-Responsive Intelligent Hydrogel Co-Delivery System Enhances Ferroptosis for Triple-Negative Breast Cancer Therapy.

PURPOSE: Triple-negative breast cancer (TNBC) lacks effective therapeutic targets. Aurisin A (AA), a natural sesterterpenoid, shows anti-TNBC potential but is limited by poor water solubility. This study aimed to develop a tumor microenvironment (TME)-responsive co-delivery hydrogel to enhance AA efficacy. METHODS: AA was complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD) to form AA@HP-β-CD, which was co-loaded with acetazolamide (ACZ) into a triple-responsive injectable hydrogel (PCG). The anti-TNBC mechanism was investigated using HCC1937 cells, focusing on ferroptosis induction. In vivo antitumor efficacy and safety were evaluated in a xenograft nude mouse model. RESULTS: AA@HP-β-CD significantly improved AA solubility and stability. Mechanistically, AA induced ferroptosis in TNBC cells by upregulating HSP90 and promoting GPX4 degradation, leading to glutathione depletion, iron accumulation, and lipid peroxidation. ACZ disrupted intracellular pH homeostasis, further sensitizing cells to AA-induced ferroptosis. The PCG hydrogel enabled sustained, TME-triggered drug release. In the xenograft model, intratumoral injection of PCG/ACZ/AA@HP-β-CD achieved a 76.3% tumor inhibition rate with no observable toxicity to major organs. CONCLUSIONS: The TME-responsive PCG/ACZ/AA@HP-β-CD hydrogel integrates drug solubilization, intelligent delivery, and dual-mechanism enhancement. The combination of AA-induced ferroptosis via the HSP90/GPX4 axis and ACZ-mediated pH disruption represents a promising strategy for TNBC therapy with good biosafety.