Targeting chemokine-driven metastasis in non-small cell lung cancer: Development and evaluation of chemokine nanosponges for therapy.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, with a poor prognosis and high metastasis rate. Metastasis involves complex mechanisms, including chemokine secretion by tumor-associated macrophages (TAMs). Using single-cell RNA sequencing (scRNA-seq), we identified enhanced chemokine secretion by M2-type TAMs in metastatic lesions, with CCL20 emerging as a key target. We designed a CCL20-adsorbing nanosponge by engineering macrophages with high CCR6 expression and extracting their membranes. This nanosponge combines targeting ability and chemokine adsorption capacity, enabling precise treatment of high-CCL20 tumors. Additionally, we encapsulated the Toll-like receptor 7/8 agonist R848 within the CCR6-modified macrophage membrane (CCR6-MM) to polarize M2-type TAMs to the M1 phenotype, reducing CCL20 secretion and transforming the immunosuppressive tumor microenvironment. In vitro and in vivo experiments validated the therapeutic potential of the CCR6-MM and R848 combination, demonstrating biocompatibility, macrophage polarization efficacy, and dual inhibitory effects on tumor growth and metastasis. Our findings highlight the potential of chemokine nanosponges as a novel therapeutic strategy for NSCLC metastasis.