A variety of colloid stabilizers and cryoprotectants confer improved nanoparticle (NP) colloidal stability and redisperability. However, discounted tumor targetability, delivery efficacy and possible side effects limit the application in vascular delivery of NPs. Here we present water-soluble silk sericin (SS) not only as a material for the preparation of NPs, but also both a dispersion stabilizer and a cryoprotectant. In the absence of any stabilizers, SS-based NPs (SSC@NPs) can resist the adsorption of serum proteins, preventing the formation of particle agglomerates. Following freeze-drying without addition of cryoprotectants, SSC@NPs powder can be easily resuspended into NP dispersion with a nearly monodispersed distribution. Additionally, SSC@NPs do not result in acute toxicity in mice at a dose of 400 mg/kg with a slow injection. Moreover, doxorubicin (DOX)-loaded SSC@NPs (DOX-SSC@NPs) diminish the biodistribution of DOX in the heart, mitigating DOX-induced cardiotoxicity of mice without compromising therapeutic efficacy. Our results suggest that the self-stabilized SSC@NPs could be a secure and effective drug carrier for intravenous administration when deprived of protective agents.During manufacturing process such as freeze-drying, or interaction with complex fluids like blood, NPs for systemic drug delivery need to be highly dispersible and structurally intact. In this work, we have demonstrated the self-stability of SSC@NPs subjected to biological media and freeze-drying. This study represents the first work showing water-soluble SS could both act as a dispersion stabilizer and a cryoprotectant due to its hydrophilicity. Plus, good in vivo biocompatibility of SSC@NPs has been confirmed. Therefore, it may be promising that water-soluble SS can be generally used as a safe biomaterial against serum adsorption.