A bimetallic dual-targeting nanoplatform for combinational ferroptosis activation/epigenetic regulation/photothermal therapy against breast cancer and tumor microenvironment remodeling

Restricted by the complex intracellular ferroptosis regulatory networks, single ferroptotic therapy against breast cancer (BC) yields limited therapeutic outcomes. Therefore, novel combination modes are being widely attempted; however, the interactions between different treatments are still less studied. Herein, we propose a combinational pattern by constructing a novel nanoplatform (T-FeCo/P) composed of Panobinostat (histone deacetylase inhibitor)-loaded iron (Fe)/cobalt (Co)-based metal-organic framework with surface modification of telmisartan for dual 4T1 cell/cancer-associated fibroblast (CAF) targeting. T-FeCo/P exhibits good photothermal performance and forcefully triggers cellular ferroptosis, and the dopant of Fe realizes stronger ferroptosis activation than the corresponding single-metal system. Interestingly, for the first time, Panobinostat is elucidated to promote ferroptosis by inhibiting SLC7A11 transcription and regulating thioredoxin binding protein 2 (TBP2)/thioredoxin (Trx) axis. For tumor microenvironment (TME) remodeling, T-FeCo/P specifically kills CAFs, thus destroying extracellular matrix and retarding C-X-C motif chemokine ligand 12 (CXCL12) secretion, which are beneficial to intratumoral drug penetration and cytotoxic T lymphocyte infiltration. Also, this CAF elimination probably sensibilizes ferroptosis by regulating neurofibromatosis type 2 (NF2)-yes associated protein (YAP) pathway and reducing myeloid-derived suppressor cell infiltration. Our experimental data support T-FeCo/P's tumoricidal activity thanks to the combined ferroptosis activation, epigenetic regulation, photothermal therapy and TME re-education, providing a mighty pattern for BC treatment and constituting a substantial addition to ferroptosis sensitization.