Micro-RNA signatures have emerged as advantageous biomarkers for disease prediction opening the route for the development of more direct and accurate therapies. There is an urgent need for reliable tools which can offer fast, highly sensitive, and selective detection of multiple miRNAs in complex matrices as opposed to the conventional techniques. Here, we demonstrate a nanophotonic biosensor with potential multiplexing capabilities based on interferometric bimodal nanowaveguides (BiMW) for ultrasensitive detection of microRNAs in complex media. Concretely, the BiMW biosensor has been employed for the detection and quantification of miR-181a at attomolar concentrations (LOD = 23 aM) directly, and for the first time, in human urine samples of bladder cancer patients with no need for prior sample purification or amplification steps. We demonstrate the extreme selectivity of our methodology for miR-181a detection showing the discrimination of homologous sequences at single nucleotide mismatch and its pre-miRNA. A significant overexpression of miR-181a in bladder cancer patients was appreciated when compared with healthy controls, suggesting the implication of this miRNA in bladder cancer. Our results show that the BiMW biosensor can be used as an ultrasensitive and specific diagnostic tool by the early and fast detection and quantification of microRNAs for the prediction of diseases (such as cancer) with well-defined microRNA signatures.