Mitochondrial-Targeting Zwitterionic Nanomedicine Based on Tertiary Amine N-oxide Polymers for Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive behavior, lack of therapeutic targets, and poor prognosis. The PI3K/AKT/mTOR pathway is highly activated in TNBC, making it a promising therapeutic target. Conventional PEGylated nanocarriers often face challenges, such as accelerated blood clearance and lysosomal trapping. To overcome these limitations, we developed a zwitterionic block copolymer, poly(2-(N-oxide-dimethylamino)ethyl methacrylate)-block-poly(ε-caprolactone) (OPDMA-PCL), via one-pot living anionic polymerization followed by postmodification. Compared with poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) micelles, the OPDMA-PCL micelles exhibited prolonged systemic circulation, improved tumor targeting, and negligible immunogenicity. OPDMA-PCL micelles exhibited mitochondria-targeting properties in vitro. Loaded with gambogenic acid (GNA), OPDMA-PCL-GNA induces apoptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR pathway. In vivo, OPDMA-PCL-GNA achieved 91.2% tumor growth inhibition in xenograft models without systemic toxicity. This work establishes zwitterionic OPDMA-PCL micelles as a promising platform for TNBC therapy, overcoming key limitations of PEGylated systems while enabling organelle-specific drug delivery.