Endoplasmic Reticulum-Targeting Iridium(III) Nanosonosensitizer Amplifies Immunogenic Cell Death for Boosted Tumor Sono-Immunotherapy

Reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress in sonodynamic therapy (SDT) can elicit immunogenic cell death (ICD)-initiated antitumor immunity for augmented sono-immunotherapy. However, unsatisfactory sonodynamic activity and mediocre ER stress induction ability of sonosensitizers essentially restrict SDT efficacy and ICD stimulation. Herein, a versatile ER-targeting Iridium(III) nanosonosensitizer is developed as superior ICD inducer for boosted tumor sono-immunotherapy. An ingenious cholic acid (CA)-functionalized Iridium(III) sonosensitizer Ir-CA is well-designed and skillfully crosslinked with human serum albumin (HSA) to form nanosonosensitizer HSA@Ir-CA. With high stability, favorable tumor-targeting ability, and reduction-responsiveness, HSA@Ir-CA preferentially accumulates in tumor sites for enhanced cellular uptake, followed by rapid disassembly responding to intracellular reductive environment. The uncaged Ir-CA can selectively accumulate in ER and precisely disrupt ER with in situ produced type I and II ROS upon US irradiation for a high-efficiency SDT. Moreover, the maximized ER stress eminently amplifies ICD to evoke robust systemic antitumor immunity, inhibiting the growths of primary/distant tumor, lung metastasis, and tumor recurrence. This ER-targeting SDT combined with immune checkpoint inhibitor (alpha PD-L1) further achieves reinforced therapeutic outcome against immunologically "cold" tumor. The study presents an effective paradigm to optimize SDT efficacy and amplify ICD-initiated immune responses for boosted sono-immunotherapy. Benefiting from favorable tumor-targeting accumulation, enhanced cellular uptake and GSH-responsive release of HSA@Ir-CA, ER-localized Ir-CA can produce dual type I and II ROS upon US irradiation to precisely disrupt ER, contributing to a high-efficiency SDT performance. Moreover, the intensified ER stress can eminently amplify ICD to stimulate robust systemic innate and adaptive antitumor immunity for boosted tumor sono-immunotherapy. image