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

Abstract 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 (αPD‐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.