An inhalable nanozyme for STING blockade to treat radiation-induced lung injury

Radiation-induced lung injury (RILI), including radiation pneumonitis (RP) and radiation-induced pulmonary fibrosis (RIPF), represents a major dose-limiting complication in thoracic radiotherapy. Acute RP constrains radiotherapy implementation, while RIPF causes irreversible pulmonary dysfunction. During ionizing radiation, the STING pathway is upregulated, and oxidative stress is induced in macrophages, promoting acute RP and resulting in late RIPF. In this study, an inhalable ferrous nanozyme encapsulating rosmarinic acid, termed FeRAzyme, was developed to address RILI induced by radiotherapy. Rosmarinic acid was rationally selected through molecular docking and dynamics simulations, revealing its non-covalent binding to STING at residues Ser243-Tyr245-Leu259-Glu260-Asn211, which blocks STING phosphorylation. After screening of a metal-based nanozyme library, FeRAzyme showed remarkable catalase- and superoxide dismutase-mimetic activities, efficiently scavenging reactive oxygen species and thus attenuating radiation-induced oxidative damage. Administered via inhalation, FeRAzyme suppressed STING phosphorylation and alleviated oxidative stress in macrophages, thus inhibiting proinflammatory cytokine secretion. Both in vitro and in vivo studies demonstrated that FeRAzyme effectively restored macrophage homeostasis and ameliorated both acute RP and myofibroblast activation without systemic toxicity. This work establishes a dual-functional STING-inhibitory nanozyme strategy for mitigating RILI, offering a promising approach for radioprotection in thoracic cancer radiotherapy.