Polyamine-Modified Poly(aspartic acid) for mRNA Delivery with <i>In Vivo</i> 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 <i>in vivo</i> 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 <i>in vitro</i> and <i>in vivo</i> mRNA transfection efficiency. We synthesized 24 polymers and identified three <i>N</i>,<i>N</i>'-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). <i>In vivo</i> 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.