Biomimetic Nanoparticles for Targeted Lung Cancer Immunotherapy via Specific Clearance of High Potassium

Lung cancer is one of the most common cancers and is the leading cause of cancer death. Recent studies have shown that high potassium ion concentrations in the lung cancer tumor microenvironment (TME) can inhibit antitumor immunity through the induction of tumor-associated macrophages (TAMs) into the M2-like phenotype. Given that crown ethers can specifically bind to potassium ions, we constructed a biomimetic pH-sensitive nanoparticle system that uses a liposome encapsulating crown ether as a core drug and the lung cancer cell membrane was employed as the outer coating (CCM-LP@crown-ether). CCM-LP@crown-ether could remove potassium ions and skew M2 macrophages toward the M1-like phenotype in a pH-dependent manner, which enhanced the ability of macrophages to phagocytose and induce tumor cell apoptosis in vitro. Intravenous injection of CCM-LP@crown-ether targeted and cleared specific potassium ions in the tumor and showed good biosafety. Importantly, CCM-LP@crown-ether increased the M1/M2 ratio, reduced MDSC infiltration, and promoted the function and quantification of CD8+ T cells in the tumor microenvironment after intravenous administration, which restored antitumor immunity and effectively inhibited tumor growth in vivo. Furthermore, CCM-LP@crown-ether achieved an enhanced antitumor effect in vivo when combined with an anti-PD-1 antibody (α-PD-1) and prolonged the survival time of tumor-bearing mice. Overall, CCM-LP@crown-ether demonstrated the potential for clinical applications in lung cancer immunotherapy.