At present, there is a great need for the development of new tumor pH-shiftable nanoparticles that are effective to reduce side effects, enhance active tumor focusing, improve the cellular uptake, and nuclear/cytoplasmic targeting of chemotherapy and gene therapeutic. Hence, we designed novel solid lipid nanoparticles (SLN) and liposomes (Lip) to deliver microRNA and antineoplastic agent, respectively. The designed SLN and liposomes incorporating microRNA and anticancer drugs in the core, which is surrounded by lipids modified with peptide T (a ligand plus a cell-penetrating peptide) and a nucleus-targeted sequence of peptide R as the inner shell. Moreover, coating a pH-responsive polymer (PGA-PEG) on the outer layer of Lip-TR (PGA-Lip-TR) and SLN-T (PGA-SLN-T) can protect the peptide T and R from degradation by peptidases during systemic circulation and enhance directing to the acidic tumor sites. Collectively, these pH-shiftable nanoparticles may provide a novel and potential strategy for anticancer therapy.