Glutathione-responsive deformable manganese-based nanomedicines for enhanced tumor-specific chemotherapy

Improving the efficiency of drug delivery and minimizing drug-related toxicities and side effects have consistently remained key goals for tumor-specific chemotherapy. However, the intricate in vivo biological barriers not only impede the efficient accumulation of nanomedicines in tumors but also trigger premature drug leakage, ultimately resulting in chemotherapy failure. Herein, glutathione-responsive deformable manganese-based nanomedicines (DMNs) were constructed. Endowed with the property of glutathione-responsive stiffness transformation, the prepared DMNs could overcome in vivo delivery barriers, including those related to in vivo distribution, cellular uptake, and tissue penetration. Concomitantly, the synchronous but separate delivery of Mn²⁺ and dopamine (DA) allowed for the in situ triggering of Mn-DA formation, thereby enabling osteosarcoma (OS) oxidative damages. In vitro and in vivo experiments reveal that their enhanced cellular uptake, multicellular spheroid penetration, and tumor accumulation, increased by 17.64-fold, 2.25-fold and 1.6-fold, compared to that of the stiff counterpart, respectively. Additionally, an excellent specific chemotherapy efficacy with tumor growth inhibition was realized in a mice OS model, by intravenous administration of DMNs. In conclusion, glutathione-responsive deformable manganese-based nanomedicines demonstrate clinical potential by addressing the limitations of precision manganese and dopamine delivery and achieving enhanced tumor-specific chemotherapy for osteosarcoma.