Cathepsin B, a cysteine protease, is linked to tumor progression and metastasis due to its elevated expression in cancers. This study explores a targeted therapy using nitroxoline (NTX), a reversible cathepsin B inhibitor, encapsulated within hollow MnO₂ nanoparticles (H-MnO₂) as both a drug carrier and chemodynamic agent. Functionalization with cetuximab (Cmab) enables selective targeting of EGFR-expressing tumors, enhancing therapy through combined cathepsin B inhibition and chemodynamic action. Hollow MnO₂ nanoshells were synthesized via a modified Stöber method and characterized by TEM and DLS, confirming a uniform spherical morphology (103.45 nm diameter, ~15 nm shell thickness, PDI: 0.1 ± 0.1, zeta potential: -47.07 ± 2.31 mV). The nanoshells degraded within 120 min in 10 mM glutathione (GSH), demonstrating tumor microenvironment responsiveness. NTX was encapsulated in PEG-modified MnO₂ nanoshells (H-MnO2-PEG/NTX) and conjugated with Cmab for EGFR targeting, achieving 11.3 ± 0.4% loading capacity and 63.40 ± 2.2% encapsulation efficiency. Synergistic ROS generation increased the chemodynamic effect fourfold, while cathepsin B inhibition significantly reduced cell migration and extracellular matrix degradation. H-MnO-PEG/NTX/Cmab offers a promising dual-action strategy for repurposing NTX as a cathepsin B inhibitor while leveraging MnO₂-mediated chemodynamic effects, addressing therapeutic limitations in triple-negative breast cancer.