Regarding cancer, innovative therapeutic approaches are needed for achieving a complete cure, since the conventional approaches are not satisfactory. The use of nucleic acids for modifying gene and protein levels in specific cells is one of the most promising approaches for cancer therapy, since it corrects the underlying cause of the disease. However, delivering various nucleic acids to their intracellular target sites is a difficult task, since they need to traverse the plasma membrane in order to be effective. Unlike conventional low molecular weight drugs, nucleic acids are large, hydrophilic and susceptible to degradation. Therefore, a sophisticated gene delivery system is required to protect and efficiently deliver these molecules to their target sites. We have been developing a series of innovative gene delivery systems based on our original design of a multifunctional envelope-type nano device (MEND). A MEND could be optimized at various levels to efficiently and safely deliver different nucleic acids to their target sites in specific cells in the body. We focused mainly on improving biodistribution after systemic administration as well as improving intracellular trafficking so as to achieve the maximum effect. Here, we summarize our efforts to develop various versions of MENDs for efficient gene delivery in vitro and in vivo. The focus is on the use of MENDs for the treatment of cancer through applying the concept of active targeting as well as passive targeting. We also summarize the applicability of a MEND system for use in cancer immunotherapy. The MEND system described here is expected to extend the therapeutic applications of nucleic acids for the treatment of various currently incurable diseases, including cancer.