Recent years have seen great advances in the development of synthetic self-assembling molecular systems. Designing out-of-equilibrium architectures, however, requires a more subtle control over the thermodynamics and kinetics of reactions. We propose a new mechanism for enhancing thermodynamic drive of DNA strand displacement reactions whilst barely perturbing forward reaction rates -introducing mismatches in an internal location within the initial duplex. Through a combination of experiment and simulation, we demonstrate that displacement rates are strongly sensitive to mismatch location and can be tuned by rational design. By placing mismatches away from duplex ends, the thermodynamic drive for a strand-displacement reaction can be varied without significantly affecting the forward reaction rate. This hidden thermodynamic driving motif is ideal for the engineering of nonequilibrium systems that rely on catalytic control and must be robust to leak reactions.One of the signature features of living systems is that they operate continuously, expending free energy, rather than relaxing to equilibrium. Key molecular components are not consumed by these reactions but recovered -they act as catalysts. 1 Examples include metabolic enzymes, signal-processing kinases, molecular motors, polymerases and even nucleic acids undergoing replication, transcription and translation. 2 Designing synthetic analogues of such complex molecular systems is a key goal of nanotechnology. This task is complicated by the requirements that reactions must be thermodynamically favourable to proceed while stable equilibrium states that lock up the key catalytic components, and accidental leak reactions, must be avoided. Overall reaction thermodynamics and kinetics must therefore be carefully tuned.Due to its predictable base-pairing interactions, DNA has proved to be a remarkable material for the construction of static nanoscale structures 3-7 and systems that perform single-shot computations. 8,9 Continuouly operating dynamic systems, including reaction network architectures 9-11 and synthetic molecular machinery, 12-14 have also been developed, but the state of the art is far from the power and flexibility of natural analogs.Toehold-mediated strand displacement (TMSD) 15 and toehold exchange, 16 illustrated in Fig. 1, are the key reactions underlying much of DNA nanotechnology. In these processes, an invading strand replaces another strand in a duplex by competing for base pairs. A