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Development of high\u2010performance mRNA delivery systems with enhanced transfection efficiency and a safety profile will further fulfill their therapeutic potential and expedite their translation. The synthesis of \u201cfour\u2010in\u2010one\u201d highly branched poly(\u03b2\u2010amino ester)s (O\u2010LhPAEs) is reported by integrating the essential components of lipid nanoparticles (LNPs) for spleen\u2010selective mRNA enrichment and nebulization treatment of silicosis. 60 O\u2010LhPAEs with distinct branched structure and chemical composition, including tertiary\/quaternary amines, cholesterol moieties, zwitterionic species, and hydrophobic alkyl tails, are synthesized using sequential Michael addition, ring\u2010opening, and nucleophilic substitution reactions. The unique topological structure and chemical composition collectively enhanced O\u2010LhPAEs\/mRNA polyplex serum resistance, cellular uptake, and endosomal escape. The optimal O\u2010LhPAE, 20%b\u20103C\u20102P12, exhibits up to 93.1% mRNA transfection across 11 different cell types, including epithelial cells, fibroblasts, cancer cells, stem cells, neurological cells, and astrocytes. Biodistribution study reveals that 20%b\u20103C\u20102P12\/mRNA polyplexes are mainly enriched in the spleen following systemic administration. Through nebulization, 20%b\u20103C\u20102P12 mediated high Tbx2 mRNA expression in the lungs of silicosis mice, effectively restoring lung functions. This study not only establishes a strategy for development of LNP\u2010like O\u2010LhPAEs but also provides promising candidates for highly safe, efficient, and spleen\u2010selective mRNA delivery and nebulization treatment of silicosis.<\/jats:p>","DOI":"10.1002\/adma.202414991","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T11:25:45Z","timestamp":1743593145000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Highly Branched Poly(\u03b2\u2010amino ester)s for Efficient mRNA Delivery and Nebulization Treatment of Silicosis"],"prefix":"10.1002","volume":"37","author":[{"given":"Haiyang","family":"Yong","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an 710004 China"},{"name":"School of Chemical Engineering and Technology Xi'an Jiaotong University  Xi'an 710049 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