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

Immunotherapy is an advanced therapeutic strategy ofcancer treatmentbut suffers from the issues of off-target adverse effects, lack ofreal-time monitoring techniques, and unsustainable response. Herein,an ultrasmall Au nanocluster (NC)-based theranostic probe is designedfor second near-infrared window (NIR-II) photoluminescence (PL) imaging-guidedphototherapies and photoactivatable cancer immunotherapy. The probe(Au(44)MBA(26)-NLG for short) is composed of atomicallyprecise and NIR-II emitting Au(44)MBA(26) NCs (hereMBA denotes water-soluble 4-mercaptobenzoic acid) conjugated withimmune checkpoint inhibitor 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol (NLG919) via a singlet oxygen (O-1(2))-cleavable linker. Upon NIR photoirradiation,the Au(44)MBA(26)-NLG not only enables NIR-II PLimaging of tumors in deep tissues for guiding tumor therapy but alsoallows the leverage of photothermal property for cancer photothermaltherapy (PTT) and the photogenerated O-1(2) forphotodynamic therapy (PDT) and releasing NLG919 for cancer immunotherapy.Such a multiple effect modulated by Au(44)MBA(26)-NLG prompts the proliferation and activation of effector T cells,upshifts systemic antitumor T-lymphocyte (T cell) immunity, and finallysuppresses the growth of both primary and distant tumors in livingmice. Overall, this study may provide a promising theranostic nanoplatformtoward NIR-II PL imaging-guided phototherapies and photoactivatablecancer immunotherapy.