From copper Ion flood to lipoylation Collapse: An NIR-II-Responsive CD44-directed nanoplatform for Two-Pronged Strike on Triple-Negative breast cancer

A CD44-targeted, NIR-II-responsive nanoplatform (CuS@ZIF-8/HA NPs) was developed for TNBC therapy. • Acidic TME triggers ZIF-8 decomposition, releasing Cu 2+ for sustained mitochondrial copper overload. • Cu + drives lipoylated DLAT oligomerization, the core event of cuproptosis. • NIR-II photothermal therapy (55.6 °C) synergizes with cuproptosis for enhanced tumor ablation. • In vivo : pronounced tumor suppression without relapse or toxicity. Triple-negative breast cancer (TNBC) lacks targetable receptors and rapidly expels cytotoxic copper via ATPase copper–transporting alpha/beta (ATP7A/B) pumps, rendering conventional cuproptosis inducers ineffective. We report an acid-activatable, CD44-directed nanoplatform (CuS@ZIF-8/HA NPs) that converts NIR-II irradiation into a synchronized mitochondrial “copper flood–heat shock” event. In the acidic tumor microenvironment, ZIF-8 decomposes and releases Cu 2+ , which is reduced to cytotoxic Cu + , triggering oligomerization of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), the core driver of cuproptosis. Concomitant ferredoxin 1 (FDX1) protein degradation serves as a downstream biochemical marker of cuproptotic injury. The photothermal effect (55.6 °C at 1 W cm −2 ) simultaneously accelerates copper release, amplifies oxidative damage, and ablates cells by hyperthermia. In 4 T1 tumor mice model, eight i.v. doses (10 mg kg −1 ) plus NIR-II light achieved profound tumor suppression without relapse or systemic toxicity, outperforming either monotherapy. Thus, CuS@ZIF-8/HA NPs turns NIR-II light into a spatially confined cuproptotic-photothermal double hit, offering a safe, precise, and translatable strategy against therapy-refractory TNBC. Download: Download high-res image (174KB) Download: Download full-size image