The efficient recovery of low temperature waste heat, representing from 25% up to 55% of the energy losses in industrial processes, still remains a challenge and even Organic Rankine Cycles (ORCs) experience a strong efficiency decay in such a low temperature operating range (T < 150 °C). In similar heat transfer processes, several nanofluids have been proposed as a solution for increasing heat transfer efficiency, but they produced only moderate enhancements of the heat transfer efficiency in comparison with pure fluids. This paper aims at numerically assessing the potential gain in efficiency deriving from the application of an unconventional type of nanoparticles, the metal-organic heat carriers (MOHCs), in the ORC field. In comparison with standard nanoparticles, these MOHCs make it possible to extract additional heat from the endothermic enthalpy of desorption, with a theoretically high potential for boosting the heat transfer capacity of ORC systems. In this paper a numerical model was developed and customized for considering the adsorption/desorption processes of the pure fluid R245fa (pentafluoropropane) combined with a crystal structure for porous chromium terephthalate (MIL101). The R245fa/MIL101 nanofluid behavior was experimentally characterized, defining proper semi-emipirical correlations. Then, an optimization procedure was developed, combining the numerical model with a PSO algorithm, to optimize the thermodynamic conditions in the ORC so as to maximize the contribution of desorption/absorption processes. The results confirm the increase in net power output (+2.9% for 100 °C) and in expander efficiency (+2.4% for 100 °C) at very low heat source temperature. The relevance of tuning the operating cycle and the nanofluid properties is also demonstrated.