Tailoring Highly Branched Poly(β-amino ester)s for Efficient and Organ-Selective mRNA Delivery

• DOI: 10.1021/acs.nanolett.4c02440
• Publication Date: 2024-07-16T18:22:41Z
• Authors: Haiyang Yong; Lixin Lin; Zhili Li; Rui Guo; Chenfei Wang; Shuai Liu; Dezhong Zhou
• Keywords: Delivery system

Development of mRNA therapeutics necessitates targeted delivery technology, while the clinically advanced lipid nanoparticles face difficulty for extrahepatic delivery. Herein, we design highly branched poly(β-amino ester)s (HPAEs) efficacious organ-selective through tailoring their chemical compositions and topological structures. Using an "A2+B3+C2" Michael addition platform, a combinatorial library 219 HPAEs with varied backbone structures, terminal groups, branching degrees are synthesized. The structures provide enhanced serum resistance significantly higher expression in vivo. amine determine organ-selectivity following systemic administration: morpholine facilitates liver targeting, ethylenediamine favors spleen delivery, methylpentane enables to liver, spleen, lungs simultaneously. This study represents comprehensive exploration structure–activity relationship governing both efficiency by HPAEs, suggesting promising candidates treating various organ-related diseases.