Chemodynamic therapy (CDT) based on cascade catalytic nanomedicine has emerged as a promising cancer treatment strategy. However, most of the reported cascade catalytic systems are designed based on symmetric- or co-assembly of multiple catalytic active sites, in which their functions are difficult to perform independently and may interfere with each other. Especially in cascade catalytic system that involves fragile natural-enzymes, the strong oxidation of free-radicals toward natural-enzymes should be carefully considered, and the spatial distribution of the multiple catalytic active sites should be carefully organized to avoid the degradation of the enzyme catalytic activity. Herein, a spatially-asymmetric cascade nanocatalyst is developed for enhanced CDT, which is composed by a Fe₃O₄ head and a closely connected mesoporous silica nanorod immobilized with glucose oxidase (mSiO₂-GOx). The mSiO₂-GOx subunit could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H₂O₂ for subsequent Fenton reaction under the catalysis of Fe₃O₄ subunit in the tumor microenvironment. Taking the advantage of the spatial isolation of mSiO₂-GOx and Fe₃O₄ subunits, the catalysis of GOx and free-radicals generation occur at different domains of the asymmetric nanocomposite, minimizing the strong oxidation of free-radicals toward the activity of GOx at the other side. In addition, direct exposure of Fe₃O₄ subunit without any shelter could further enhance the strong oxidation of free-radicals toward objectives. So, compared with traditional core@shell structure, the long-term stability and efficiency of the asymmetric cascade catalytic for CDT is greatly increased by 138%, thus realizing improved cancer cell killing and tumor restrain efficiency.

As the first-line technology, micelles play a pivotal role in in vivo delivery of theranostic agents because of their high biocompatibility and universality. However, in complex physiological environments (extreme dilution, pH, and oxidation or reduction, etc.), they generally suffer from structural instability and insufficient protection for encapsulated cargos. It is urgent to reinforce the structural stability of the micelles at the single-micelle level. By using the FDA-approved Pluronic F127 surfactants and indocyanine green (ICG) bioimaging agents as model, herein, we propose the silane-crosslinking assisted strategy to reinforce the structural stability of the single-micelle. Different from the traditional silane hydrolysis under the harsh experimental conditions (acidic, alkaline, and high temperature hydrothermal, etc.), the ICG loaded F127@SiO₂ hybrid single-micelles (ICG@H-micelles) with controllable sizes (15–35 nm) are synthesized at neutral pH and room temperature, which is crucial for the maintenance of the physicochemical properties of the encapsulated cargos. With the ultra-thin SiO₂ (< 5 nm) at hydrophilic layer of the single-micelle, the structural and fluorescence stability of ICG@H-micelles are much higher than the conventional micelle (ICG@micelles) in the simulated physiological environments of dilution, oxidation or reduction, and low pH. Because of the high structural and fluorescence stability, the ICG@H-micelles also exhibit longer duration time in the tumor and gastrointestinal tract bioimaging.