Artemisinin (ART) is well known as an antimalarial drug, and it can also be used to treat inflammation as well as cancer. Although many researchers have reported the antitumor activity of ART, most of these studies were investigated in vitro. In addition, ART is sparingly soluble in water, limiting its clinical relevance in drug development. Based on the data from our preliminary study, ART is not cytotoxic at low micromolar concentrations. Thus, we hypothesized that smart nanocarriers are beneficial for not only increasing the solubility of ART but also elevating the concentration of the drug at the target, thereby inducing the ideal antitumor effect. In this article, a reversibly activatable cell-penetrating peptide ((HE)(10)-G(5)-R-6 or HE-R-6) was introduced to modify artemisinin (ART)-loaded liposomes (ART-Lip-HE-R-6) against tumors, and in vitro and in vivo performance were investigated. ART-Lip-HE-R-6 exhibited sustained release under different pH conditions. The internalization and cytotoxicity of liposomes were enhanced at low pH, i.e., 6.5, after modification with HE-R-6 versus nonmodified liposomes. Moreover, a longer retention time in tumors could be observed in the ART-Lip-HE-R-6 group, followed by higher efficiency of tumor suppression. In conclusion, Lip-HE-R-6 might be a promising delivery system for ART in cancer therapy. (C) 2020 Elsevier Inc. All rights reserved.