The combination of two or more drugs with different mechanisms of action is a promising strategy for circumventing multidrug resistance (MDR). However, the antitumor effect of nanosystems is usually limited due to the simultaneous release of different payloads at a single location rather than at their respective sites of action. Herein, we report a GSH and pH dual responsive nanoplatform encapsulated with doxorubicin (DOX) and resiquimod (R848) (GPNP) for combinatorial chemotherapy against cancer cells with drug resistance. GPNP possesses a core-shell structure wherein the polymer shell detaches in the acidic and sialic acid (SA)-rich environment. This leads to the release of R848 into the tumor microenvironment (TME), thereby reprogramming M2 macrophages into M1 macrophages and exposing the core CS(DOX)-PBA to kill MCF-7/ADR cells. Additionally, the nitric oxide (NO) generated by M1 macrophages can suppress the P-glycoprotein (P-gp) expression to reduce the efflux of chemotherapy drugs, thus playing a combined role in overcoming MDR. In vitro studies have demonstrated the effectiveness of GPNP in reprogramming M2 macrophages and inducing apoptosis in MCF-7/ADR cells, resulting in enhanced antitumor efficacy. This work proposed an effective combination strategy to combat chemoresistance, providing new insights into the development of innovative combinatorial therapies against MDR tumors.

A chitosan-based nanoplatform that responds to both GSH and pH levels was developed, which helped to overcome MDR through the integration of chemotherapy and macrophage polarization.