Herein, reduction-responsive disintegratable nanoclusters (NCs) were prepared as a novel nanovehicle for targeted drug delivery. The NCs, with a diameter of ∼170 nm, were self-assembled from hydrophobically modified and iRGD decorated hydroxyethyl starch (iRGD-HES-SS-C18). DOX was loaded into the NCs as a model drug. DOX@iRGD-HES-SS-C18 NCs can disintegrate into smaller ones and release DOX under reduction stimuli. Due to the ligand-receptor binding interactions between iRGD and integrin αV, DOX@iRGD-HES-SS-C18 NCs can specifically bind to the cell membranes of HepG-2 and 4T1 cells (integrin αV positive), resulting in enhanced cellular uptake as compared to DOX@HES-SS-C18 NCs. After cellular internalization, the NCs were transported to endosomes/lysosomes in which the reductive environment triggered the disintegration and DOX release. As a consequence, DOX@iRGD-HES-SS-C18 NCs exhibited an enhanced antitumor effect as compared to DOX@HES-SS-C18 NCs and free DOX, in an in vitro antitumor activity study. The reduction-responsive disintegratable NCs reported here were proved to be a safe and efficient nanoplatform, holding significant translation potential for tumor-targeted drug delivery.