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Most cancer therapies are suffering from side effects to varying degrees, which might compromise the body functions and long-term health of patients. Balancing treatment efficacy and side effects has become a priority. Inspired by the concept that cellular ion homeostasis can lead to apoptosis, we developed a novel therapeutic strategy by incorporating the K+ transporter valinomycin into liposomes (Lipo-VM). Valinomycin is a naturally occurring polypeptide showing good biodegradation in vivo with reduced long-term side effects. Lipo-VM facilitates the K+ efflux of cells and triggers a caspase-dependent pathway of apoptosis by causing the collapse of mitochondrial membrane potential. With the help of a liposome-based nano-delivery system, Lipo-VM shows enhanced cell uptake and accumulation at the tumor site, which results in significant inhibition of tumor growth in a liver cancer model. The proposed valinomycin-anchored liposome provides an efficient and safe approach for cancer therapy. [Display omitted] • A cancer therapeutic system of valinomycin-anchored liposomes (Lipo-VM) is proposed. • Lipo-VM shows enhanced cell uptake and accumulation at the tumor site. • Cell membrane fused Lipo-VM facilitates K+ efflux of cells inhibiting tumor growth. • A caspase-dependent pathway of apoptosis is proposed. • Lipo-VM provides an efficient and safe approach for cancer therapy. [ABSTRACT FROM AUTHOR]