A dual-responsive metal-polyphenol nanomedicine based on targeting LAT1 via levodopa and ROS amplification for precise treatment of breast cancer

Breast cancer remains a major global health challenge, with triple-negative breast cancer (TNBC) posing a particular therapeutic dilemma due to its lack of targetable receptors and reliance on chemotherapy, which is often thwarted by drug resistance. To overcome these limitations, we developed a novel metal-polyphenol nano-platform (DLF@NPs) via a one-pot coordination assembly of L-dopa (L-DA), doxorubicin (DOX), and ferrous ions (Fe 2+ ). This GSH/pH-dual-responsive nanoparticle exploits the overexpression of L-type amino acid transporter 1 (LAT1) on breast cancer cells for targeted delivery and tumor-specific enrichment, effectively addressing the off-target toxicity and resistance associated with free DOX. Upon internalization into the acidic and high-GSH tumor microenvironment, DLF@NPs rapidly disassemble, releasing their payload. The liberated DOX not only exerts its apoptotic effect but also activates NADPH oxidases (NOXs) to elevate intracellular H 2 O 2 levels. This endogenous H 2 O 2 supply fuels a Fenton reaction catalyzed by the co-released Fe 2+ , generating highly toxic hydroxyl radicals. Furthermore, L-DA reduces the resultant Fe 3+ back to Fe 2+ , establishing a catalytic cycle that robustly amplifies reactive oxygen species (ROS). The resultant ROS burst synergizes with DOX by inducing severe mitochondrial damage, leading to potentiated apoptosis. In summary, this work proposes a novel targeted nanoplatform that utilizes the synergy between chemodynamic therapy and chemotherapy to provide a promising strategy for combating drug-resistant breast cancer.