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Here, a size\u2010tunable micro\u2013nano liposome system, PCAL@TM, is designed for targeted delivery of paclitaxel (PTX) and oxygen to lung tumors. PTX\u2010loaded corosolic acid (CA) nano\u2010liposomes (PCAL, 100\u00a0nm) are anchored to the surface of oxygenated perfluorotributylamine (TBA)\u2010loaded multivesicular liposomes (TM, 10\u00a0\u00b5m) via the biotin\u2013avidin interactions with matrix metalloproteinase\u20109 (MMP\u20109) cleavable linker. After intravenous administration to lung tumor\u2010bearing mice, the distribution amount of PCAL@TM in the lungs is extremely higher than that in the liver and spleen. The MMP\u20109\u2010sensitive PCAL@TM can decouple into nano\u2010PCAL and micro\u2010TM in tumors; while, TMs enable breaking into smaller vesicles under vascular pressure, and release oxygen leading to the downregulation of HIF\u20101\u03b1 and platelet\u2010activated TGF\u2010\u03b2. Meanwhile, PCAL can penetrate deeply into tumor by the tumor\u2010targeted\u2010penetrable CA liposomes, to promote the reduction of inflammation levels and enhance PTX\u2010induced immunogenic cell death (ICD). Together, these results lead to the reversals of chemoresistance and tumor immunosuppressive, achieving significant improvement in PTX chemotherapy and \u03b1\u2010PD\u20101 immunotherapy. The PCAL@TM system presents a novel strategy to enhance the efficiency of nano\u2010drug delivery and the outcome of combined therapy for lung tumor.<\/jats:p>","DOI":"10.1002\/smll.202409593","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T05:17:43Z","timestamp":1744780663000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Size\u2010Tunable Micro\u2013Nano Liposomes: Enhanced Lung Targeting and Tumor Penetration for Combination Treatment of Lung Cancer"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-412X","authenticated-orcid":false,"given":"Yueying","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Smart Drug Delivery Ministry of Education (Fudan University) Department of Pharmaceutics School of Pharmacy Fudan University  Shanghai 201203 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