A dual pH/ROS-sensitive nanoplatform blocking NETs formation and co-delivering paclitaxel for potent therapeutic efficacy against triple-negative breast cancer and lung metastasis

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high recurrence rates, limited therapeutic options, and a strong propensity for spontaneous lung metastasis. Increasing evidence indicates that neutrophil extracellular traps (NETs) significantly promote TNBC progression, immune evasion, and metastatic dissemination, highlighting NET inhibition as a promising therapeutic strategy. Herein, we developed a dual pH/ROS-responsive nanoplatform (pH/ROS@(PTX/SIV)) constructed from acetylated dextran (Ace-DEX) and phenylboronic acid-modified dextran (PBAP-DEX) and further functionalized with the fibronectin-targeting peptide CREKA to achieve tumor-specific accumulation. This nanoplatform enables controlled, microenvironment-responsive release of paclitaxel (PTX) and the neutrophil elastase inhibitor sivelestat (SIV) in acidic and oxidative tumor tissues. The optimized nanoparticles exhibited uniform size, high encapsulation efficiencies, and robust dual-responsive drug release. <i>In vitro</i>, CREKA modification markedly enhanced cellular uptake and tumor-targeting efficiency, while the dual-loaded system showed superior cytotoxicity against TNBC cells. In orthotopic TNBC mouse models, pH/ROS@(PTX/SIV) significantly suppressed primary tumor growth, prolonged survival, and critically inhibited spontaneous lung metastasis. Mechanistically, the formulation effectively blocked NET formation both in isolated primary neutrophils and in tumor tissues, thereby disrupting NET-mediated pro-metastatic signaling. Furthermore, the nanoplatform displayed favorable systemic safety with negligible organ toxicity. This dual-responsive, NET-modulating nanoplatform provides a potent and safe therapeutic strategy for combating TNBC and preventing its metastasis, offering strong potential for clinical translation.