Unleashing the Potent Antitumor Force: A Reactive Oxygen Species (ROS) Storm Formation by Ultrasound—Activatable Metal Nanosonosensitizers

ABSTRACT Reactive oxygen species (ROS)‐mediated tumor therapy, which induces oxidative stress damage for precise oncolysis, represents a novel antitumor strategy. However, the overexpression of glutathione (GSH) in the tumor microenvironment (TME) forms a strong antioxidant barrier, rapidly scavenging ROS and repairing oxidative damage, thus limiting the efficacy of conventional ROS‐based therapies. Metal nanosonosensitizers, activated by ultrasound and penetrating deeply into the TME, offer a promising solution when combined with glutaminase1 (GLS1) inhibitors to overcome GSH‐mediated defenses. This study innovatively constructs a biomimetic metal nanosonosensitizer, CRIM, with a copper sulfide as core, encapsulating IR780 and IPN60090, coated with tumor cell membranes. CRIM specifically accumulates in tumor cell mitochondria, where ultrasound activation triggers efficient ROS generation while depleting GSH levels by direct consumption and indirect synthesis. This synergistic GSH depletion disrupts the tumor antioxidant system, sustaining ROS accumulation and triggering a ROS storm. The “ROS generation‐GSH depletion‐exacerbated oxidative stress” feedback loop induces immunogenic cell death (ICD). Additionally, copper ion released from CRIM induces cuproptosis, synergizing with ROS‐mediated cytotoxicity to enhance therapeutic efficacy. This approach triggers a ROS storm via multi‐pathway synergy, induces comprehensive tumor destruction, and activates systemic immunity, thereby unleashing a potent antitumor force and offering a new direction for cancer treatment.