Engineering a TME-responsive hollow ZnzMnx-zOy-based nanoplatform for cancer theranostic applications

Abstract

This study engineered a tumor microenvironment (TME)-responsive theranostic nanosystem by employing hollow zinc-doped manganese oxide (H-Zn_zMn_x-zO_y) nanostructures. Doping Zn²⁺ ions into the Mn_xO_y matrix induces lattice distortion, increases microstrain, and improves surface heterogeneity, thereby enhancing drug-loading capacity and catalytic performance. Meanwhile, optimization of the nanoplatform at Z = 0.05 yielded a high specific surface area (S_BET = 49.11 m² g⁻¹) and a mesoporous structure. Furthermore, the surface was modified using chitosan cross-linked with tripolyphosphate (Chi-TPP) to enhance biocompatibility and colloidal stability under physiological conditions. Adsorption studies revealed a maximum PTX loading capacity of 151.069 mg g⁻¹ under the optimal conditions (160 ppm PTX, 0.9 mg mL⁻¹ nanoplatform, and 7 h contact time), with a loading efficiency of 89.7 %. The in vitro release studies demonstrated that PTX release was highly selective under tumor-mimicking conditions, including acidic pH, elevated temperature, 100 μM H₂O₂, and 10 mM glutathione (GSH), resulting in 86 % drug release. In contrast, less than 10 % release occurred under normal physiological conditions, confirming the TME-specific responsiveness of the nanoplatform. Moreover, in phantom experiments using T₁-weighted magnetic resonance imaging (MRI), the longitudinal relaxivity (r₁) increased15-fold (7.74 vs. 0.52 mM⁻¹ s⁻¹) under simulated TME conditions, which was attributed to the release of Mn²⁺ ions via catalytic degradation. Cytotoxicity assays indicated that non-specific cell toxicity was markedly reduced by Chi-TPP surface modification while retaining efficient PTX delivery capability. Collectively, the H-Zn_zMn_x-zO_y@Chi-TPP@PTX nanosystem serves as a multifunctional platform for TME-responsive hypoxia modulation and MRI bioimaging, enabling targeted drug delivery (TDD) and controlled release.