Multi-payload Antibody-Drug Conjugates for Photothermal Dynamic and Chemotherapy of HER2-positive Breast Cancer

HER2-positive breast cancer is highly aggressive and has a poor prognosis in clinical treatment primarily due to the overexpression of HER2 protein. Trastuzumab can significantly improve the therapeutic outcome for HER2-positive breast cancer, but 70% of patients develop drug resistance. Trastuzumab-drug conjugates have emerged as a promising modality in the treatment of HER2-positive breast cancer, while their therapeutic efficacy remains limited. Herein, we report a multi-payload trastuzumab conjugate, QC-AA@Tra, prepared by attaching an AIPH-bearing NIR-II fluorophore (Q3) to trastuzumab via nucleophilic substitution. After intravenous administration, QC-AA@Tra selectively accumulates at tumor sites. Under 808 nm laser irradiation, it produces a strong photothermal–dynamic effect through thermal release of nitrogen gas and free radicals from AIPH. Combined with trastuzumab’s targeting, this leads to marked suppression of HER2-positive BT474 xenograft tumors in mice. Our design may offer a powerful and universal modality for precise diagnosis and treatment of HER2-positive malignant tumors.