APE1‐Triggered Inhalable Microsphere (ATIM) for In Situ Non‐Small Cell Lung Cancer Theranostics

Distinguishing benign from malignant pulmonary nodules remains a major clinical challenge, where misdiagnosis may lead to either delayed cancer treatment or unnecessary invasive procedures. Here, we report apurinic/apyrimidinic endonuclease 1 (APE1)-triggered inhalable microsphere (ATIM) for non-small cell lung cancer (NSCLC) theranostics by leveraging inhalation delivery and homotypic targeting to accelerate the local enrichment of DNA tetrahedrons (TDNs) in pulmonary tumors, which enables in situ NSCLC theranostics. Upon intracellular recognition of the APE1, entropy-driven catalytic circuits are activated, triggering nanoparticle aggregation to amplify fluorescence for real-time tumor imaging and releasing miR-126-3p to induce tumor cell apoptosis by suppressing ADAM9. In a mouse orthotopic NSCLC model, the tumor-bearing group showed a fluorescent intensity 1.67-fold higher than the healthy group, and the pulmonary accumulation of the ATIM system via inhalation was 3.12-fold higher than that via intravenous injection, while ATIM therapy significantly reduced the tumor burden to a relative area of 45.3 ± 1.6%. Our results demonstrate that ATIM achieves accurate discrimination between benign and malignant pulmonary nodules while effectively inducing apoptosis in tumor cells. This theranostic system offers a promising dual-functional platform for precision diagnosis and targeted therapy in early-stage NSCLC.