There is an urgent need for developing nanocarrier of excellent biocompatibility which can selectively release drugs at desired locations that can increase intratumoral drug concentration and reduce side effects. Herein, we developed a highly biocompatible nanocarrier made of oxidized starch in delivering doxorubicin (DOX) for enhanced anti-cancer therapy. The 30% oxidized starch can spontaneously self-assemble into 30–50 nm spherical nanoassemblies under physiological concentrations. DO30 nanoassemblies possessed negligible toxicity in several cell lines and ICR mice, in contrast to severe toxicity of synthetic polyacrylic acid (PAA), both of which are carboxyl-abundant polymers. The biocompatible DO30 was further decorated with cyclic RGD (Arg-Gly-Asp-Phe-Cys) peptides via PEG linker to target αvβ3 integrin overexpressed on HepG2 cells. RGD-PEG-DO30/DOX demonstrated an enhanced tumor-targeting ability and anti-cancer property in vitro and in vivo. In general, RGD-oxidized starch nanoassemblies showed a great potential as a new type of safe and effective nanocarrier for anti-cancer therapy.