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

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.