RNA interference (RNAi) is a powerful approach for silencing oncogenes; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained delivery. Here, we describe a novel approach to overcome these limitations using mesoporous silicon particles loaded with nanoparticles (i.e., liposomes) containing small interfering RNA (siRNA) targeted against oncoprotein that contributes to cancer cell survival. This delivery method resulted in sustained gene silencing for at least 3 weeks with substantial reduction of tumor growth with no overt toxicities in two independent orthotopic mouse models of ovarian cancer following a single intravenous administration of mesoporous silicon particles loaded with liposomal EphA2-siRNA.