Size‐Tunable Micro–Nano Liposomes: Enhanced Lung Targeting and Tumor Penetration for Combination Treatment of Lung Cancer

Abstract The inefficient delivery of nanocarriers and drug resistance seriously limit therapeutic effects of lung cancer. Here, a size‐tunable micro–nano liposome system, PCAL@TM, is designed for targeted delivery of paclitaxel (PTX) and oxygen to lung tumors. PTX‐loaded corosolic acid (CA) nano‐liposomes (PCAL, 100 nm) are anchored to the surface of oxygenated perfluorotributylamine (TBA)‐loaded multivesicular liposomes (TM, 10 µm) via the biotin–avidin interactions with matrix metalloproteinase‐9 (MMP‐9) cleavable linker. After intravenous administration to lung tumor‐bearing mice, the distribution amount of PCAL@TM in the lungs is extremely higher than that in the liver and spleen. The MMP‐9‐sensitive PCAL@TM can decouple into nano‐PCAL and micro‐TM in tumors; while, TMs enable breaking into smaller vesicles under vascular pressure, and release oxygen leading to the downregulation of HIF‐1α and platelet‐activated TGF‐β. Meanwhile, PCAL can penetrate deeply into tumor by the tumor‐targeted‐penetrable CA liposomes, to promote the reduction of inflammation levels and enhance PTX‐induced immunogenic cell death (ICD). Together, these results lead to the reversals of chemoresistance and tumor immunosuppressive, achieving significant improvement in PTX chemotherapy and α‐PD‐1 immunotherapy. The PCAL@TM system presents a novel strategy to enhance the efficiency of nano‐drug delivery and the outcome of combined therapy for lung tumor.