Activatable Mn2+-Armed nanoagonist augments antitumor immunity in colorectal cancer: A NIR-II Photonic neoadjuvant paradigm

Postoperative recurrence frequently occurs in patients with colorectal cancer (CRC) due to residual microtumors and host cellular immune dysfunction, leading to major setbacks in clinical outcomes and CRC staging. As an increasingly prevalent therapeutic option for CRC patients, neoadjuvant chemoradiotherapy bears unmet chal-lenges of limited tumor targeting and common side effects of gastrointestinal reaction and radiodermatitis. It is highly desirable to develop neoadjuvant treatment paradigms that impart both tumor-targeting accuracy and protection against recurrence of resectable CRC. Here we report a versatile photo-regulated nanoagonist of plasmonic gold blackbody (AuPB) with a polydopamine (PDA) coating carrying manganese ion (Mn2+) payloads (AuPB@PDA/Mn). When armed with second near-infrared (NIR-II) light, AuPB@PDA/Mn with broad-band localized surface plasmon resonance generates local hyperthermia and discharges Mn2+ ions, which evidently amplify the effects of immunogenic cell death in tumor cells and activate the cyclic GMP-AMP synthase/stim-ulator of interferon genes pathway in dendritic cells (DCs), hence potentiating the maturation of DC and the secretion of type I interferon in a synergistic way. Matured DCs undertake the task of tumor antigen presentation as the crosstalk to adaptive immunity. As such, the administration of AuPB@PDA/Mn coupled with NIR-II laser irradiation has eminently augmented the infiltration of CD8+ T cells as well as the development of memory CD8+ T cells in colorectal tumor models, substantiating enhanced immunomodulatory efficacy against primary and recurrent CRC. Our strategy highlights the potency of an integrated NIR-II photothermal and immunoregulatory modality by photo-activate delivery of Mn2+ ions, as a neoadjuvant paradigm for presurgical tumor debulking and against postoperative tumor recurrence.