Lung Tissue‐Targeting STING mRNA‐LNPs Inhibits Tumor Progression and Induces Systemic Anti‐Tumor Immunity in Non‐Small Cell Lung Cancer

Abstract The STING pathway holds immunotherapeutic promise but faces challenges in tumor‐specific delivery and systemic toxicity. A lung‐targeting peptide (APWHLSAQYSRT)‐modified lipid nanoparticle (LNP) system (LT‐STING‐LNPs) is developed to deliver STING mRNA for non‐small cell lung cancer (NSCLC) treatment. These spherical, stable LNPs exhibited high mRNA encapsulation efficiency. In vitro, LT‐STING‐LNPs induced potent STING overexpression in lung cells, inhibiting NSCLC cell proliferation, migration, and invasion. In vivo, LNPs demonstrated superior lung tropism, enabling targeted STING activation in pulmonary tissue without systemic distribution. In murine lung metastasis models, treatment drastically reduced metastatic burden, suppressed tumor proliferation (Ki‐67), and inhibited epithelial‐mesenchymal transition (Vimentin). Notably, the platform shows excellent safety with no organ toxicity. LT‐STING‐LNPs synergized robustly with anti‐PD1 therapy, achieving near‐complete metastasis inhibition. Mechanistically, this is driven by STING‐TBK1‐IRF3 signaling activation, inflammatory cytokine (IFN‐α, IL‐1β, CXCL10) production, and immune microenvironment remodeling, including increased CD8+ T cell and M1 macrophage infiltration. This targeted, safe, and highly effective immunotherapy strategy represents a promising advancement for NSCLC, leveraging synergistic STING pathway activation and immune checkpoint blockade.