Engineering Au₄₄ Nanoclusters for NIR-II Luminescence Imaging-Guided Photoactivatable Cancer Immunotherapy

Immunotherapy is an advanced therapeutic strategy of cancer treatment but suffers from the issues of off-target adverse effects, lack of real-time monitoring techniques, and unsustainable response. Herein, an ultrasmall Au nanocluster (NC)-based theranostic probe is designed for second near-infrared window (NIR-II) photoluminescence (PL) imaging-guided phototherapies and photoactivatable cancer immunotherapy. The probe (Au₄₄MBA₂₆-NLG for short) is composed of atomically precise and NIR-II emitting Au₄₄MBA₂₆ NCs (here MBA denotes water-soluble 4-mercaptobenzoic acid) conjugated with immune checkpoint inhibitor 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol (NLG919) via a singlet oxygen (¹O₂)-cleavable linker. Upon NIR photoirradiation, the Au₄₄MBA₂₆-NLG not only enables NIR-II PL imaging of tumors in deep tissues for guiding tumor therapy but also allows the leverage of photothermal property for cancer photothermal therapy (PTT) and the photogenerated ¹O₂ for photodynamic therapy (PDT) and releasing NLG919 for cancer immunotherapy. Such a multiple effect modulated by Au₄₄MBA₂₆-NLG prompts the proliferation and activation of effector T cells, upshifts systemic antitumor T-lymphocyte (T cell) immunity, and finally suppresses the growth of both primary and distant tumors in living mice. Overall, this study may provide a promising theranostic nanoplatform toward NIR-II PL imaging-guided phototherapies and photoactivatable cancer immunotherapy.