Nucleic acid coated photothermal nanoregulator for multiple therapy of drug-resistant breast cancer

Int J Biol Macromol. 2025 May;308(Pt 2):142592. doi: 10.1016/j.ijbiomac.2025.142592. Epub 2025 Mar 27.

Abstract

Chemotherapy resistance is a leading cause of failure in cancer treatment. A variety of strategies have been investigated to overcome this resistance in cancer therapies. However, the complex microenvironment of tumor cells makes it challenging for any single approach to achieve optimal therapeutic outcomes. In this study, we modified MXene with hyaluronic acid (HA) and coloaded it with doxorubicin (DOX) and the nucleic acid miR489 to address chemotherapy resistance by inhibiting DOX efflux and enabling gene interference. The tumor-targeting capability and biocompatibility of the developed nanosystem, miR489-DOX/Ti3C2@HA-ADH (DTH489), were enhanced through the incorporation of HA. Under near-infrared radiation, MXene not only facilitates photothermal therapy but also reduces the efflux of chemotherapy drugs by down regulating the expression of P-glycoprotein. Additionally, miR489 inhibits epithelial-mesenchymal transition by suppressing the expression of Mothers Against Decapentaplegic Homolog 3, which substantially improves the sensitivity of drug-resistant cancer cells to DOX. In vitro studies confirmed that DTH489 effectively inhibited DOX-resistant breast cancer cells (MCF-7/ADM). Moreover, DTH489 exhibited substantial tumor growth suppression in a mouse model of drug-resistant breast cancer. The results of this research underscore the potential of DTH489 as a multimodal therapeutic platform that effectively reverses chemotherapy resistance in cancer.

Keywords: Drug efflux; Drug-resistant breast cancer; Gene interference.

MeSH terms

  • Animals
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Breast Neoplasms* / therapy
  • Cell Line, Tumor
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology
  • Drug Carriers / chemistry
  • Drug Resistance, Neoplasm* / drug effects
  • Epithelial-Mesenchymal Transition / drug effects
  • Female
  • Humans
  • Hyaluronic Acid / chemistry
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs* / chemistry
  • MicroRNAs* / genetics
  • Nanoparticles* / chemistry
  • Nucleic Acids* / chemistry
  • Photothermal Therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Doxorubicin
  • MicroRNAs
  • Hyaluronic Acid
  • Nucleic Acids
  • Drug Carriers