Modified Aerotaxy for the Plug-in Manufacture of Cell-Penetrating Fenton Nanoagents for Reinforcing Chemodynamic Cancer Therapy

The assemblies of anisotropic nanomaterials have attracted considerable interest in advanced tumor therapeutics because of the extended surfaces for loading of active molecules and the extraordinary responses to external stimuli for combinatorial therapies. These nanomaterials were usually constructed through templated or seed-mediated hydrothermal reactions, but the lack of uniformity in size and morphology, as well as the process complexities from multiple separation and purification steps, impede their practical use in cancer nanotherapy. Gas-phase epitaxy, also called aerotaxy (AT), has been introduced as an innovative method for the continuous assembly of anisotropic nanomaterials with a uniform distribution. This process does not require expensive crystal substrates and high vacuum conditions. Nevertheless, AT has been used limitedly to build high-aspect-ratio semiconductor nanomaterials. With these considerations, a modified AT was designed for the continuous in-flight assembly of the cell-penetrating Fenton nanoagents (Mn-Fe CaCO3 (AT) and Mn-Fe SiO2 (AT)) in a single-pass gas flow because cellular internalization activity is essential for cancer nanotherapeutics. The modified AT of Mn-Fe CaCO3 and Mn-Fe SiO2 to generate surface nanoroughness significantly enhanced the cellular internalization capability because of the preferential contact mode with the cancer cell membrane for Fenton reaction-induced apoptosis. In addition, it was even workable for doxorubicin (DOX)-resistant cancer cells after DOX loading on the nanoagents. After combining with immune-checkpoint blockers (antiprogrammed death-ligand 1 antibodies), the antitumor effect was improved further with no systemic toxicity as chemo-immuno-chemodynamic combination therapeutics despite the absence of targeting ligands and external stimuli.