Endocytic Uptake of Self‐Assembled Iridium(III) Nanoaggregates for Holistic Treatment of Metastatic 3D Triple‐Negative Breast Tumor Spheroids

Abstract Triple‐negative breast cancer (TNBC) presents a formidable challenge due to its aggressive behavior and limited array of treatment options available. This study focuses on employing nanoaggregate material of organometallic Ir(III) complexes for treating TNBC cell line MDA‐MB‐231. In this approach, Ir(III) complexes with enhanced cellular permeability are strategically designed and achieved through the incorporation of COOMe groups into their structure. The lead compound, IrL ¹ , exhibits promiscuous nanoscale aggregation in RPMI cell culture media, characterized by a stable hydrodynamic effective diameter ranging from 190 to 202 nm over 48 h. With excellent photo‐responsive contrast‐enhanced cell imaging properties IrL ¹ exhibits an outstanding IC _{50, 48h} value of 36.05± 0.03 n m when irradiated with 390 nm light in MDA‐MB‐231 (IC _{50, 48 h} of Cisplatin is 5.29 µ µ ). In cell, investigation confirms that IrL ¹ nanoaggregates internalization via energy‐dependent endocytosis undergo ferroptosis and ROS mediated cell death in MDA‐MB‐231 cells. Further, these in vivo studies using NOD‐SCID mice confirmed that IrL ¹ exhibits a tendency to ablate tumors inoculated in mice models at therapeutically relevant doses. Thus, this comprehensive approach holds promise for expanding the repertoire of organometallic Ir(III) nanoaggregates with adaptable characteristics, thereby advancing their clinical utility of nanomedicine in the holistic treatment of metastatic 3D triple‐negative breast tumor spheroids.