RNA interference (RNAi) technology can specifically silence the expression of a target gene and has emerged as a promising therapeutic method to treat cancer. In the present study, we showed that natural halloysite nanotube (HNT)-assisted delivery of an active small interfering RNA (siRNA) targeting receptor-interacting protein kinase 4 ( ) efficiently silenced its expression to treat bladder cancer. The HNTs/siRNA complex increased the serum stability of the siRNA, increased its circulation lifetime in blood, and promoted the cellular uptake and tumor accumulation of the siRNA. The siRNA markedly down-regulated expression in bladder cancer cells and bladder tumors, thus inhibiting tumorigenesis and progression in three bladder tumor models (a subcutaneous model, an in situ bladder tumor model, and a lung metastasis model), with no adverse effects. Thus, we revealed a simple but effective method to inhibit bladder cancer using silencing, indicating a promising therapeutic method for bladder cancer.