Highly Branched Poly(β‐amino ester)s for Efficient mRNA Delivery and Nebulization Treatment of Silicosis

Abstract

Abstract mRNA therapeutics hold tremendous promise for disease prevention and treatment. Development of high‐performance mRNA delivery systems with enhanced transfection efficiency and a safety profile will further fulfill their therapeutic potential and expedite their translation. The synthesis of “four‐in‐one” highly branched poly(β‐amino ester)s (O‐LhPAEs) is reported by integrating the essential components of lipid nanoparticles (LNPs) for spleen‐selective mRNA enrichment and nebulization treatment of silicosis. 60 O‐LhPAEs 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‐opening, and nucleophilic substitution reactions. The unique topological structure and chemical composition collectively enhanced O‐LhPAEs/mRNA polyplex serum resistance, cellular uptake, and endosomal escape. The optimal O‐LhPAE, 20%b‐3C‐2P12, 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‐3C‐2P12/mRNA polyplexes are mainly enriched in the spleen following systemic administration. Through nebulization, 20%b‐3C‐2P12 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‐like O‐LhPAEs but also provides promising candidates for highly safe, efficient, and spleen‐selective mRNA delivery and nebulization treatment of silicosis.