NIR‐II Excitation Phototheranostic Platform for Synergistic Photothermal Therapy/Chemotherapy/Chemodynamic Therapy of Breast Cancer Bone Metastases

Abstract To improve bone metastases treatment efficacy, current strategies are focused on the integration of chemotherapy with phototheranostic. However, the success of phototheranostic approaches is hampered by the limited tissue penetration depth of near‐infrared‐I (NIR‐I) light (700–900 nm). In this study, a NIR‐II (1000–1700 nm) excitation phototheranostic (BTZ/Fe 2+ @BTF/ALD) is presented for NIR‐II fluorescence imaging and NIR‐II photoacoustic imaging‐guided NIR‐II photothermal therapy (PTT), chemotherapy, and chemodynamic therapy (CDT) of breast cancer bone metastases. This phototheranostic is developed by integrating a dopamine‐modified NIR‐II absorbing donor–acceptor–donor small molecule (BBT‐FT‐DA), the boronate anticancer drug bortezomib (BTZ), and Fe 2+ ions, as CDT catalysts, into an amphiphilic PEGylated phospholipid modified with the bone‐targeting ligand alendronate. In acidic and hydrogen peroxide (H 2 O 2 ) over expression tumor microenvironment, the boronate–catechol linkage is cleaved and BTZ and Fe 2+ ions are released to initiate the Fenton reaction, that is, chemotherapy and CDT, respectively, are initialized. It is confirmed using the murine 4T1 bone metastasis model that BTZ/Fe 2+ @BTF/ALD significantly suppresses the progression of tumor cells in the bone tissue via a synergistic NIR‐II PTT/chemotherapy/CDT effect. Overall, this work provides fresh insights to guide the development of NIR‐II phototheranostics for breast cancer bone metastases.