Single-Atom Engineering of a Sonosensitizer to Enable Mitochondrial Sabotage for Potent STING-Mediated Antitumor Immunity

Abstract

While sonodynamic therapy (SDT) holds promise for localized tumor ablation, its ability to elicit systemic antitumor immunity remains inadequate due to weak immunogenic priming. Herein, we report a dual-engine single-atom-engineered nanoplatform (MNSe) that converts SDT into a robust immunological reprogrammer via irreversible mitochondrial sabotage. By tuning the central heteroatom of an isoindigo derivative, selenium substitution significantly amplifies spin–orbit coupling, maximizing ultrasound-triggered reactive oxygen species (ROS) generation. Conjugation with a triphenylphosphonium moiety precisely localizes this amplified oxidative stress to mitochondria. Rationally coupling atom-enhanced ROS with precise subcellular targeting effectively exceeds the biological damage threshold and overcomes endogenous repair mechanisms. The resulting organelle disruption triggers substantial cytosolic leakage of mitochondrial DNA to robustly activate the cGAS-STING pathway. In vivo, this drives interferon-β secretion and CD8+ T-cell infiltration to inhibit primary and distant tumors and to establish durable immunological memory against tumor recurrence, providing a powerful paradigm for spatiotemporally controllable cancer immunotherapy.