Delivery is the major hurdle thwarting the therapeutic potential of RNA medicines. While all siRNA drugs on the market target the liver, the lung offers a variety of currently undruggable targets which could be treated with RNA therapeutics. Hence, my lab rationally designs inhalable and biocompatible nanocarriers for efficient siRNA delivery to the lung. Poly(beta-amino ester)s are biodegradable polymers capable of promoting nucleic acid delivery and can be tailormade to investigate structure–function relationships. We combine Design-of-Experiments (DoE) with Molecular Dynamics Simulations and Machine Learning (ML) to accelerate the discovery and optimization process of these siRNA nanocarriers. Our previous results show the feasibility of synthesizing oleylamine-modified spermine-based poly(β-amino ester)s (PBAEs) that efficiently encapsulate siRNA into nanoparticles and the low polymer excess avoids problems of toxicity and polymer-induced side effects. The PBAE-based polyspermines successfully delivered siRNA for gene silencing in 2D cultures and Transwell® air-liquid-interface cultures. Additionally, Boc-protected PBAE-based polyspermines mediated therapeutic gene silencing of mutated KRAS resulting in impaired cell migration. In an effort to compare polymer backbones, polyacrylamide (PAA)-based polyspermines were synthesized and resulted in more efficient siRNA delivery and gene silencing in Transwell® air-liquid-interface cultures compared with Lipofectamine but had a much more favorable safety profile in vitro and in vivo. After intratracheal administration to mice, the PAA-based polyplexes were efficiently taken up by Type II pneumocytes and successfully evaded recognition by macrophages in the lung.