Scaffolds functionalized with matrix metalloproteinase-responsive release of miRNA for synergistic magnetic hyperthermia and sensitizing chemotherapy of drug-tolerant breast cancer

Combining hyperthermia and chemotherapy for maximum anticancer efficacy remains a challenge because drug-tolerant cancer cells often evade this synergistic treatment due to drug resistance and asynchronous drug release. In this study, multifunctional scaffolds were designed to efficiently treat drug-tolerant breast cancer by improving the sensitization of breast cancer cells and synchronizing anticancer drug release with magnetic hyperthermia. The scaffolds contained microRNA-encapsulated matrix metalloproteinase-cleavable liposomes, doxorubicin-encapsulated thermoresponsive liposomes and Fe₃O₄ nanoparticles. The scaffolds could release microRNA specifically to improve the sensitization of breast cancer cells to anticancer drugs. The scaffolds also showed excellent hyperthermia effects under alternating magnetic field irradiation. Moreover, doxorubicin release was synchronized with magnetic hyperthermia. <i>In vitro</i> and <i>in vivo</i> studies demonstrated that the scaffolds effectively reduced drug resistance and eliminated doxorubicin-tolerant MDA-MB-231 cells through the synergistic effect of magnetic hyperthermia and sensitizing chemotherapy. Additionally, the scaffolds could support the proliferation and adipogenic differentiation of stem cells for adipose tissue regeneration after killing cancer cells at a late therapeutic stage. These composite scaffolds offer an innovative strategy for treating breast cancer, with synergistic anticancer effects and regenerative functions.