GSH-Responsive Heterodimeric Dual-Targeted Nanomedicine Modulates EMT to Conquer Paclitaxel-Induced Invasive Breast Cancer Metastasis

Paclitaxel (PTX), although effective against primary breast cancer, presents formidable clinical challenges due to severe toxicity and pro-metastatic potential, a critical concern as distant metastasis causes 90% of breast cancer-related deaths. To address these limitations, we designed and prepared a tumor microenvironment-responsive nanoprodrug, PTX-SS-3'HPT@RGD-HA NPs, that engineered RGD peptide-modified hyaluronic acid (HA) nanocarriers encapsulating the antimetastatic 3'-hydroxy pterostilbene (3'HPT) and PTX heterodimer linked by a glutathione (GSH)-cleavable disulfide bond. These nanoparticles targeting CD44 and αvβ receptors overexpressed in aggressive breast cancer cells and synergized enhanced permeability and retention effects with receptor-mediated endocytosis, facilitating superior tumor-specific drug deposition and GSH-activated payload release <i>in vitro</i> and <i>in vivo</i>. Moreover, PTX-SS-3'HPT@RGD-HA NPs achieved excellent tumor growth inhibition while mitigating systemic toxicity and metastatic risks in 4T1 tumor-bearing mice. Mechanistically, 3'HPT counteracted PTX-induced epithelial-mesenchymal transition by downregulating MMP-9/N-cadherin and restoring E-cadherin expression, thereby neutralizing PTX-triggered pro-metastatic effects. This study pioneers a dual-targeted, toxicity-shielding nanoplatform that simultaneously improves therapeutic efficacy and addresses chemotherapy-driven metastasis, offering a revolutionary strategy for managing highly invasive breast cancer.