Though PEGylation has been widely used to enhance the accumulation of liposomes in tumor tissues through enhanced permeability and retention (EPR) effects, it still inhibits cellular uptake and affects intracellular trafficking of carriers. Active targeting molecules displayed better cell selectivity but were shadowed by the poor tumor penetration effect. Cell penetrating peptides could increase the uptake of the carriers but were limited by their non-specificity. Dual-ligand system may possess a synergistic effect and create a more ideal drug delivery effect. Based on the above factors, we designed a multistage liposome system co-modified with RGD, TAT and cleavable PEG, which combined the advantages of PEG, specific ligand and penetrating peptide. The cleavable PEG could increase the stability and circulation time of liposomes during circulation. After the passive extravasation to tumor tissues, the previously hidden dual ligands on the liposomes were exposed in a controlled manner at the tumor site through exogenous administration of a safe reducing agent l-cysteine. The RGD specifically recognized the integrins overexpressed on various malignant tumors and mediated efficient internalization in the synergistic effect of the RGD and TAT. In vitro cellular uptake and 3D tumor spheroids penetration studies demonstrated that the system could not only be selectively and efficiently taken up by cells overexpress ingintegrins but also penetrate the tumor cells to reach the depths of the avascular tumor spheroids. In vivo imaging and fluorescent images of tumor section further demonstrated that this system achieved profoundly improved distribution within tumor tissues, and the RGD and TAT ligands on C-R/T liposomes produced a strong synergistic effect that promoted the uptake of liposomes into cells after the systemic administration of l-cysteine. The results of this study demonstrated a tremendous potential of this multistage liposomes for efficient delivery to tumor tissue and selective internalization into tumor cells.