Genetic engineering promises to improve the therapeutic potency of mesenchymal stem cells which have emerged as versatile cell therapies in regenerative medicine, cancer treatment, and immunomodulation. However, hMSCs are highly recalcitrant to the introduction of exogenous nucleic acids (transfection), rendering it difficult to engineer large banks of cells expressing specific genetic modifications. We approach this ex vivo gene delivery problem by considering the nexus between the interfacial properties of stem cell culture substrates and the physicochemical attributes of engineered polyplexes. We will explore the interplay between surface chemical cues and polyplex properties by examining transfection outcomes on surface-engineered substrates of diverse chemical functionalities and brush architectures. These efforts will help us understand how cellular morphology, adhesion and proliferation are influenced by substrate features such as polymer brush composition, brush thickness, mechanical compliance, wettability, surface charge and interfacial roughness. Further, we will explore whether enhanced cell adhesion and proliferation will translate into improved polyplex uptake and editing efficiency. Ultimately, these results will inform the design of biomaterials that safely and efficiently induce genetic modifications that enhance the therapeutic potential of biomanufactured MSCs.