Breaking Tumor Chemoresistance via METTL3 Regulation Enhanced by Sequential Delivery of Dexamethasone

The frequent occurrence of chemoresistance in breast tumors remains a challenge to achieving satisfactory therapeutic efficacy, and a smart drug delivery system with flexible properties is urgently needed to achieve an all-in-one combination anticancer therapy. In this study, an efficiency delivery system with a pH-triggered detachable PEG layer (sPEG) and a folic acid (FA)-modified cationic liposome core (FLip) is constructed for codelivering doxorubicin (DOX) and METTL3 siRNA (siMETTL3). The obtained codelivery nanoparticles (NPs), sPEG-FLip@DOX/siMETTL3, can maintain circulatory stability with minimized systemic toxicity, which is attributed to the negatively charged sPEG layer, and expose the positively charged FLip core in the weakly acidic extracellular environment to facilitate the internalization by MCF-7/ADR cells. Moreover, its targeting efficiency can be further enhanced by dexamethasone (Dex) pretreatment owing to the enhanced binding efficiency of FA to folate receptor α (FRα) and the reduced immune clearance of FA-functionalized NPs. After internalization via FA-FRα interactions, the positively charged FLip core induces the effective endosomal escape of codelivery NPs, accompanied by the release of DOX and siMETTL3. As a result, the levels of drug resistance-related proteins in tumors are significantly downregulated, and the enhanced chemotherapy and suppressed DOX resistance demonstrate superior tumor suppression in MCF-7/ADR tumor-bearing mice. This sequential therapy provides a reliable approach for improving cancer chemotherapy with suppressed DOX resistance by destroying the N6 methyladenosine (m6A) methylation, which may extremely benefit the future design of smart drug delivery systems.