Covalently Anti-HER2-Functionalized MOF for Targeted Chemotherapy and NIR-Activated Photothermal/Photodynamic Cancer Therapy

Metal–organic frameworks (MOFs) have emerged as versatile nanoplatforms for biomedical applications, including targeted drug delivery and protein immobilization, because of their exceptional structural tunability and functional versatility. In this study, disulfide-bearing p-nitrophenyl phosphonate (pNPP) groups were grafted onto TCPP@UiO-66-NH 2, enabling the site-specific conjugation of cutinase-anti-HER2 fusion proteins to form a tumor-targeted nanogated system. The chemotherapeutic prodrug irinotecan (CPT-11) and the synthetic fluorescent probe IR780-SPhF were coloaded into the MOF framework, exploiting elevated intracellular glutathione (GSH) levels in tumor cells to trigger precise, on-demand drug release. Under NIR irradiation, the nanoplatform integrates chemotherapy with photothermal (PTT) and photodynamic therapy (PDT), producing synergistic antitumor effects and significantly reducing tumor viability compared to monotherapy approaches. Simultaneously, the incorporated IR780-SPhF enables multimodal tumor imaging via fluorescence and photoacoustic modalities, providing a real-time diagnostic capability. Collectively, the anti-HER2-gated PTU-MOF combines targeted delivery, synergistic therapy, and theranostic functionality, offering a promising strategy for precise, controlled, and personalized cancer treatments.