Polyamine-Modified Poly(aspartic acid) for mRNA Delivery with In Vivo Lung-Targeted Ability

Polymers are widely used as mRNA delivery platforms, but their clinical translation is limited by challenges such as nonorgan-selective expression and low in vivo efficacy. Poly(amino acids), particularly poly(aspartic acid) (PAsp), have been extensively studied for drug, nucleic acid, and protein delivery due to their excellent biodegradability and biocompatibility. However, the role of aminolysis-modified PAsp in mRNA delivery remains to be fully explored. In this study, we developed a series of polyamine-aminolyzed PAsp derivatives (P-An), further functionalized with heterocyclic small molecules (P-An-M), and evaluated their in vitro and in vivo mRNA transfection efficiency. We synthesized 24 polymers and identified three N,N'-bis(3-aminopropyl)ethylenediamine (PDA)-modified PAsp derivatives that efficiently transfected Luc-mRNA in 293T cells: P-PDA, P-PDA-I, and P-PDA-BI (where I and BI represent 1H-imidazole-4-carboxylic acid and 1H-benzimidazole-4-carboxylic acid, respectively). In vivo experiments demonstrated that P-PDA, P-PDA-I, and P-PDA-BI selectively delivered mRNA to the lungs and achieved a significant level of protein expression. This work provides a promising strategy for developing polymer-based materials for mRNA lung therapy, with potential applications in treating pulmonary diseases.