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[Display omitted] • The acidic tumor microenvironment induced a geometrical shape change by amphiphilic peptide LKR nanoparticles. • The obtained targeted LKR nanoparticles were simple but effective with no modification. • Anticancer drugs can be loaded and encapsulated into LKR nanoparticles with no covalent crosslinking. • LKR nanoparticles enhanced the drug accumulation in tumor cells compared with normal mammalian cells. • LKR was used in combination with encapsulated drugs for antitumor therapy in vivo. Spatial accuracy is crucial in drug delivery, especially to increase the efficacy and reduce the side effects of antitumor drugs. In this study, we developed a simple and broadly applicable strategy in which a target peptide ligand was introduced to construct a pH-responsive drug-loading system to achieve targeted delivery and drug release in lesions. In addition to reaching the tumor tissue through passive targeting modalities such as the enhanced permeability and retention (EPR) effect, active targeting nanoparticles used RGD motifs coupled to nanocarriers to specifically bind certain integrins, such as α ν β3, which is expressed on the surface of tumor cells, to achieve active tumor cell targeting. Self-assembling peptides have significant advantages in their structural design. The amphiphilic peptide LKR could form a spherical and self-assembled nanoparticle, which encapsulated the fat-soluble antitumor drug doxorubicin (Dox) in neutral medium. The Dox-encapsulating peptide nanoparticles swelled and burst, rapidly releasing Dox in an acidic microenvironment. Flow cytometry and fluorescence detection showed that the self-assembled LKR nanoparticles enhanced the drug accumulation in tumor cells compared with normal mammalian cells. The Dox-encapsulating peptide nanoparticles exhibited desirable antitumor effects in vivo. In summary, the acidic microenvironment of tumors was used to induce drug release from a targeted peptide drug-loading system to enhance cellular uptake and therapeutic effects in situ , providing a promising therapeutic approach for the treatment of major diseases such as hepatoma. [ABSTRACT FROM AUTHOR]