This work designs an HA-GO nanocarrier co-loaded with DOX, MDR1 ASO, and MiR-489 for targeted cancer therapy. MDR1 ASO inhibits P-gp expression, MiR-489 suppresses Smad3 signaling, and DOX damages DNA. The synergistic gene and chemotherapy overcome multidrug resistance, increase drug accumulation, and induce potent cancer cell apoptosis.

Abstract

Multidrug resistance (MDR) significantly limits breast cancer chemotherapy effectiveness. Here, we engineered a hyaluronic acid–functionalized graphene oxide (HA-GO) nanocarrier for co-delivery of microRNA-489 and MDR1 antisense oligonucleotide (ASO, MB1) alongside doxorubicin (DOX). Among various nucleic acid ratios, a MiR-489:MDR1 ASO ratio of 2:1 exhibited the most potent enhancement of DOX sensitivity in MCF-7/ADM cells. This co-delivery system synergistically reduced drug resistance, increased intracellular DOX accumulation, and amplified cytotoxicity. These results highlight the optimized HA-GO platform as a promising strategy to overcome MDR in breast cancer therapy.