Planar electronics processing methods have enabled neural interfaces to become more precise and deliver more information. However, this processing paradigm is inherently 2D and rigid. The resulting mechanical and geometrical mismatch at the biotic–abiotic interface can elicit an immune response that prevents effective stimulation. In this work, a thiol–ene/acrylate shape memory polymer is utilized to create 3D softening substrates for stimulation electrodes. This substrate system is shown to soften in vivo from more than 600 to 6 MPa. A nerve cuff electrode that coils around the vagus nerve in a rat and that drives neural activity is demonstrated.