A tumor microenvironment-responsive and mannose-mediated MnO2-based nano-delivery system for synergistic targeted chemotherapy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains a formidable challenge due to its aggressive progression and the absence of established therapeutic targets. This study engineered a multifunctional, tumor microenvironment (TME)-responsive nanoplatform MnO 2 @Man/DOX, which was designed for synergistic targeted chemotherapy and TME modulation. The platform comprises a manganese dioxide (MnO 2 ) core for redox regulation and a mannose (Man) shell for active targeting and metabolic sensitization, stabilized with bovine serum albumin and sodium dodecyl sulfate. MnO 2 @Man/DOX nanoparticles are nearly spherical (289 nm) and exhibit dual-responsiveness by efficiently depleting intracellular glutathione and catalyzing endogenous hydrogen peroxide into cytotoxic hydroxyl radicals via Fenton-like reactions. In vitro, the nanoplatform demonstrated a remarkable 8-fold reduction in IC 50 (0.52 μg/mL) compared with free doxorubicin (4.2 μg/mL) in 4T1 cells. Transcriptomic analysis suggested that MnO 2 @Man/DOX is associated with TNF signaling and apoptosis-related pathways, including extrinsic, intrinsic, and endoplasmic reticulum stress-mediated programs. In vivo evaluations in 4T1 tumor-bearing mice confirmed preferential tumor accumulation and superior growth inhibition with a high biosafety profile, including a hemolysis rate below 5% and minimal systemic toxicity. By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO 2 @Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.