Charge-convertible MnO2-coated liposomal nanocarriers boost doxorubicin delivery for potentiated breast cancer chemotherapy

Efficient completion of the CAPIR (circulation, accumulation, penetration, internalization, and release) cascade is essential for nanosystems to achieve satisfactory therapeutic efficacy and prognosis. Herein, we fabricated a manganese dioxide (MnO 2 )-coated cationic liposomal nanocarrier (MnO 2 @CLDOX) for enhanced doxorubicin (DOX) delivery via a multistage strategy. The anionic MnO 2 shell conferred negative zeta potential, enabling prolonged blood circulation and reduced systemic toxicity. In the tumor microenvironment, MnO 2 selectively decomposed under acidic pH and high hydrogen peroxide, exposing cationic CLDOX and generating O 2 . Cationic CLDOX facilitated cellular uptake via electrostatic interactions with tumor cell membranes. Meanwhile, O 2 alleviated tumor hypoxia, downregulated hypoxia-inducible factor-1 α , decreased collagen deposition, and improved extracellular matrix permeability, thus boosting drug penetration. Collectively, MnO 2 @CLDOX enhanced DOX delivery efficiency through synergistic mechanisms, achieving superior therapeutic efficacy against breast cancer.