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Published on: April 17, 2012
Mass Spectrometry-Assisted High-Throughput Discovery of Lung-Specific Lipid Nanoparticles for In Vivo Protein
Ji Liu1,2, Yangyang Zhang1,2, Rui Yao1,2
1Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
Abstract:
Precise and tissue-specific delivery of proteins remains a major barrier to realizing their therapeutic potential. Here, we report a mass spectrometry-assisted high-throughput screening (MSHTS) strategy for rapid identification of lung-targeting lipid nanoparticles (LNPs). A combinatorial library of 46 thioketal-containing biodegradable lipids was synthesized via Michael addition, enabling multiplexed biodistribution profiling in a single animal. MSHTS identified BDMPA-TK12 with preferential lung accumulation for in vivo protein delivery. Proteomic analysis revealed the formation of a vitronectin-enriched protein corona that promotes receptor-mediated uptake of BDMPA-TK12 by pulmonary endothelial cells. The optimized LNP efficiently delivers functional proteins, including Cre recombinase and antioxidant DJ-1, to the lung across multiple animal species. Lung-specific delivery of DJ-1 activates MAPK signaling, mitigating ferroptosis, and inflammatory injury in acute lung inflammation. Our study establishes MSHTS as a scalable strategy for discovering tissue-selective nanoparticles and significantly advances LNP-mediated delivery of proteins for diverse biomedical applications.
