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 (Fe2+). 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 H2O2 levels. This endogenous H2O2 supply fuels a Fenton reaction catalyzed by the co-released Fe2+, generating highly toxic hydroxyl radicals. Furthermore, L-DA reduces the resultant Fe3+ back to Fe2+, 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.