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Multidrug resistance (MDR) promotes tumor recurrence and metastasis and heavily reduces anticancer efficiency, which has become a primary reason for the failure of clinical chemotherapy. The mechanisms of MDR are so complex that conventional chemotherapy usually fails to achieve an ideal therapeutic effect and even accelerates the occurrence of MDR. In contrast, the combination of chemotherapy with dual-drug has significant advantages in tumor therapy. A novel dual-drug codelivery nanosystem, which combines dual-drug administration with nanotechnology, can overcome the application limitation of free drugs. Both the characteristics of nanoparticles and the synergistic effect of dual drugs contribute to circumventing various drug-resistant mechanisms in tumor cells. Therefore, developing dual-drug codelivery nanosystems with different multidrug-resistant mechanisms has an important reference value for reversing MDR and enhancing the clinical antitumor effect. In this review, the advantages, principles, and common codelivery nanocarriers in the application of dual-drug codelivery systems are summarized. The molecular mechanisms of MDR and the dual-drug codelivery nanosystems designed based on different mechanisms are mainly introduced. Meanwhile, the development prospects and challenges of codelivery nanosystems are also discussed, which provide guidelines to exploit optimized combined chemotherapy strategies in the future. [Display omitted] • The mechanisms of multidrug resistance (MDR) and diverse dual-drug codelivery nanosystems based on different multidrug-resistant mechanisms are comprehensively summarized. • Codelivering dual-drug with different mechanisms helps to modulate the signal pathways of MDR. • Multifunctional dual-drug codelivery nanoplatforms can effectively overcome MDR and improve antitumor efficiency. • The advantages, application principles, development prospects and potential challenges of dual-drug codelivery nanosystems in overcoming MDR are discussed. [ABSTRACT FROM AUTHOR]

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 antiapoptotic defense behavior in cancerous cells. To overcome these issues, we have designed 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 not only is 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 codelivery nanosystem possesses synergistic effects on tumor inhibition, enabling significantly enhanced antitumor outcome. This work demonstrates that the codelivery 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.