GSH-pH dual-responsive engineered codoped Prussian\nblue multimodal theranostic nanoplatform induces TP53 deregulated\napoptotic death of MDA-MB-231 with enhanced T<sub>1</sub> - T<sub>2</sub>W MRI

Though\nchemotherapy is an effective clinical treatment, individual\ndrugs hardly achieve precise controlled release, causing unavoidable\nsevere side effects due to off-targeting in the absence of any receptor\nof triple negative breast cancer (TNBC). Fortunately, the emergence\nof on-demand drug-release nanoparticles allows potential alternatives\nto overcome the limitation. In this work, a dual-responsive multimodal\ntheranostic targeted smart nanoplatform has been prepared by employing\nmesoporous silica (mSiO<sub>2</sub>)-coated Dy<sup>3+</sup>, Gd<sup>3+</sup>-codoped Prussian blue nanocubes (PBNCs) with CytC as a gatekeeper\nto seal pores of mSiO<sub>2</sub> via disulfide and boronate ester\nbonds as intermediate linkers for intracellular high glutathione,\nand acidic pH responsive drug release. Hyaluronic acid has been used\nas a targeting motif, facilitating the uptake of our synthesized nanoplatform,\nwherein a cumulative drug-release profile demonstrated that the nanoplatform\nexhibits very low sustained drug release at pH 7.0 (∼20% in\n25 h), while the release gets accelerated at pH 5.0 and 8.0 mM GSH\n(∼60% in 25 h), realizing the “trigger release”\nof drug. The nanoplatform possesses excellent biocompatibility to\nHEK 293 cells, while it has high cytotoxicity (∼67%) toward\nTNBC (IC<sub>50</sub> = 35.8 μM), ascribed to synergistic chemo-phototherapeutic\neffect. An <i>in silico</i> analysis, followed by immunocytochemical\nstudies illustrate that the down-regulated TP53-BAX/BCL2 and upregulated\nCASP3 CYTS networks initiate an apoptotic cell-death mechanism. In\naddition, the nanoplatform exhibits potency as a dual-mode MRI contrast\nagent with high relaxivity (<i>r</i><sub>1</sub> and <i>r</i><sub>2</sub>) values of ∼7.84 and ∼29.3 mM<sup>–1</sup> s<sup>–1</sup>, which will be highly facilitating\nfor the diagnosis and tracking of TNBC management for personalized\nmedicine.