Abstract

Triple-negative breast cancer (TNBC) is characterized by its unfavorable prognosis and heightened propensity for metastasis. Despite paclitaxel (PTX) chemotherapy being a cornerstone of treatment, it can paradoxically promote metastasis by facilitating Padi4-mediated nuclear expulsion and triggering the RAGE/ERK pathway. In this investigation, we engineered a tumor-responsive nanoparticle platform (RAPG) capable of codelivering PTX, the Padi4 inhibitor GSK484, and a RAGE antagonist peptide (RAP). The RAPG nanoparticles exhibited redox-sensitive drug release, precise tumor localization, and deep tissue permeation. Mechanistically, RAPG suppressed histone citrullination, impeded RAGE/ERK signaling, and reinforced conventional apoptotic pathways. In both in vitro and in vivo assessments, RAPG attenuated epithelial-mesenchymal transition markers and reduced tumor invasiveness, circulating tumor cells, and lung metastasis, while enhancing treatment efficacy and prolonging survival. This study presents a promising strategy to counteract chemotherapy-induced metastasis in TNBC through concurrent inhibition of Padi4-mediated histone citrullination and RAGE/ERK signaling.