Pulmonary surfactant-based inhalable nanoparticles for folate receptor-targeted delivery and macrophage reprogramming in lung cancer

Background Lung cancer remains a leading cause of cancer-related death, and chemotherapy is often limited by systemic toxicity and insufficient drug accumulation in lung tumors. Inhalable nanomedicine offers a route to address these limitations, but nanoparticle systems remain limited by poor nebulization stability, rapid macrophage-mediated clearance, and an immunosuppressive tumor microenvironment. To address these challenges, we developed pemetrexed-modified pulmonary surfactant-based nanoparticles loaded with paclitaxel (PEM-PSNP@PTX) for inhalation therapy that targets both tumor cells and tumor-associated macrophages. The nanoparticles were formulated using clinically approved exogenous pulmonary surfactant to facilitate integration into the endogenous alveolar surfactant layer. Pemetrexed, an antifolate, was incorporated primarily as a folate receptor-targeting ligand. Results PEM-PSNP@PTX had a mean particle size of 135.3 nm and a drug loading of 17.6%, and maintained comparable particle size and drug loading before and after nebulization, indicating colloidal stability during aerosolization. After inhalation, the nanoparticles were retained in the lung for up to 48 h with limited systemic distribution. Folate receptor was expressed on lung cancer cells and on M2-polarized macrophages, and PEM-PSNP@PTX was internalized by both cell types, resulting in greater cytotoxicity in folate receptor-positive cells than in folate receptor-negative control cells. In a mouse lung cancer model, inhaled PEM-PSNP@PTX significantly suppressed tumor growth, improved survival, and caused no observable systemic toxicity compared with free paclitaxel and PLGA nanoparticles. Treatment reduced the levels of the immunosuppressive cytokines IL-10 and TGF-β while increasing the pro-inflammatory cytokines IL-12 and TNF-α in bronchoalveolar lavage fluid (BALF). In addition, PEM-PSNP@PTX increased CD86 and decreased CD206 expression within the tumor, indicating macrophage repolarization from an M2- toward an M1-like phenotype. Conclusions Inhaled PEM-PSNP@PTX effectively suppressed lung tumor growth through dual targeting of tumor cells and tumor-associated macrophages while remodeling the immunosuppressive tumor microenvironment. These findings support pulmonary surfactant-based inhalation as a promising therapeutic strategy for local treatment of lung cancer.