Efficient on-demand cuproptosis induction against triple-negative breast cancer via dual-responsive black phosphorus nanosheet

Cuproptosis, a newly identified cell death pathway, has been shown by our analyses to be closely associated with the clinical prognosis of triple-negative breast cancer (TNBC) patients and may potentially facilitate the elimination of TNBC. However, precisely and efficiently regulating cuproptosis in tumor regions in a controllable manner remains challenging. Here, a highly effective cuproptosis inducer based on black phosphorus nanosheets (BPNs@Cu@PDA, denoted as BCP) is constructed, featuring acidic and thermal-responsive copper ion release, as well as enhanced cuprous ion (Cu⁺) loading capability. Briefly, BCP efficiently increases the loading proportion of Cu⁺ via inherent surface redox reactions between phosphorus and copper ions (Cu²⁺), thereby enabling a significantly elevated cuproptosis induction ability. After accumulating at the tumor, BCP precisely releases Cu^+/2+ in response to the photo-hyperthermia and acidic microenvironment created by the dopamine modification, thereby efficiently producing reactive hydroxyl radicals (•OH) through Cu^+/2+-dependent Fenton-like reactions, which leads to significant oxidative damage in TNBC cells. The precisely released Cu^+/2+ further inhibits the production of the Fe-S cluster while causing the aggregation of succinylated proteins, leading to significantly disrupted mitochondrial function and the TCA cycle, thereby inducing significant cuproptosis and subsequent TNBC suppression (over 90 % decrease in tumor volumes) in a synergistic manner. This research presents a novel cuproptosis induction strategy specifically designed for TNBC that has negligible toxicity, which may provide insights into the clinical treatment of TNBC.