Acquired drug resistance in malignant tumors seriously hinders effective chemotherapy against cancer. The main mechanisms of drug resistance include decreased drug influx, increased drug efflux, as well as anti-apoptotic defense behavior in cancerous cells. To overcome these issues, we design a nanomedicine composed of pure doxorubicin (DOX) as the core and B-cell lymphoma-2 (Bcl-2) siRNA as the shell for synergistic cancer treatment. Between the core and shell, polyethylene glycol (PEG) and polyethylenimine (PEI) are employed to increase the stability of the core DOX NPs and facilitate siRNA coating, respectively. In this design, the siRNA is able to inhibit the expression of Bcl-2 protein which has a role of protecting cancer cells from apoptosis. DOX is not only for anticancer therapy, but also acts as a nanocarrier for Bcl-2 siRNA delivery. Our studies show that Bcl-2 siRNA and DOX are efficiently delivered into tumor cells and tumor tissues, and such a co-delivery nanosystem possesses synergistic effects on tumor inhibition, enabling significantly enhanced anti-tumor outcome. This work demonstrates that the co-delivery of tumor suppressive Bcl-2 siRNA and chemotherapeutic agents without using an excipient material as a drug carrier represents a promising therapy for enhanced cancer therapy.