The low therapeutic effect and strong side-effect are the major barriers for clinical chemotherapy. Herein, a pH-responsive nanoplatform based-silk sericin-zeolitic imidazolate framework-8 was designed for the delivery of chemotherapeutic doxorubicin (denoted as ZIF-8@DOX@SS, ZDS), which can overcome the limitation of poor circulation stability and unexpected drug leakage in blood circulation, producing a satisfactory chemotherapy. Concretely, ZIF-8 structure shows better stability and biocompatibility owing to the protection of a nature and non-toxic sericin protein. When it comes to low pH environment (e.g. in tumor cell microenvironment), the coordination effect in ZIF-8 will be broken and release DOX drugs. The nano-sized morphology endow ZDS an efficient drug uptake and significant tumor permeability efficiency. Furthermore, the tumor-specific biodegradability makes ZDS possible to realize targeted and enhanced chemotherapy. Considering all the advantages in the study, this silk sericin-based nanosystem represent a promising strategy for the design of stimuli-responsive by using natural polymer to improve the treatment effect of chemotherapy.