Efficient delivery systems are fundamental to the clinical translation of mRNA-based therapeutics and vaccines. Poly(β-amino ester) (pBAE) nanocarriers represent a versatile platform for mRNA delivery, as their chemical composition and architecture can be tuned to control encapsulation efficiency, structural stability, and interactions with biological environments. Molecular level insight are fundamental to understand the pBAE-mRNA interaction and optimally design the carrier. In this context, molecular dynamics (MD) simulations represent an elective tool of investigation and a state-of-art technique to couple experimental choice and define the optimal pBAE-mRNA encapsulation ratio. In addition to optimizing experimental design, MD enables direct observation of microscopic mechanisms that are difficult to resolve experimentally and supports the rational interpretation of macroscopic outcomes.