Immunotoxicological mechanism of a dual-targeted nanocomposite: Mitochondrial stress-driven cGAS-STING activation in lung cancer.

Abstract

Lung cancer remains a leading cause of cancer mortality. We developed a dual-targeting nanocomposite FU@TPP/BSA@MnO/UA that induces mitochondrial dysfunction and activates the cGAS-STING pathway. The nanocomposite features a BSA-Mn2 + core, a FU@TPP shell for sequential, dual-stage targeting-first recognizing P-selectin on the tumor vascular endothelium, followed by triphenylphosphine (TPP)-directed mitochondrial localization-and encapsulated ursolic acid (UA). Mechanistically, FU@TPP/BSA@MnO/UA internalizes into lung cancer cells, causing mitochondrial swelling, membrane potential loss, elevated mtROS, and an increased Bax/Bcl-2 ratio. These events trigger autophagic flux and mtDNA release into the cytoplasm, activating the cGAS-STING pathway, which leads to nuclear translocation of IRF3 and p65, upregulation of cGAS/STING, and production of IFN-γ, TNF-α, IL-1β, and IL-6. In a murine LLC xenograft model, the nanocomposite significantly suppresses tumor growth, promotes intratumoral CD8⁺ T cell infiltration, and enhances dendritic cell maturation. Notably, combination with the PD-1 inhibitor sintilimab produces synergistic antitumor efficacy without observable systemic toxicity. Collectively, FU@TPP/BSA@MnO/UA bridges mitochondrial disruption with innate immune activation, offering a promising dual-mechanism strategy for lung cancer treatment and checkpoint immunotherapy enhancement.