Due to antimicrobial resistance and the adverse health effects that follow broad and inappropriate use of antibacterial agents, new classes of antibacterials with broad and strong bactericidal activity and safety for human use are urgently required globally, increasingly so with the onset of climate change. However, R&D in this field is known to be rarely profitable, unless a cost-effective, flexible, and convenient platform that ensures the production of workable candidate antibacterials can be developed. To address this issue, inorganic nanomaterials have been considered for their bactericidal activities, yet further investigations of composition crystalline modifications and/or surface biomaterial coatings are still required to provide effective and safe antibacterial nanoparticles. In this study, we developed a plug-in system comprising a spark plasma reactor and a flow heater under nitrogen gas flow to supply precursor inorganic nanoparticles (Cu−Te configuration) that can be modulated in-flight at different temperatures. From antibacterial and toxicological assays in both in vitro and in vivo models, bactericidal and toxicological profiles showed that the plug-in system-based platform can be used to identify key parameters for producing safe-by-design agents with antibacterial activity [>88% (in vitro) and >80% (in vivo) in antibacterial efficiency] and safety (>65% in in vitro viability and >60% in in vivo survival rate).

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.

ARTICLE HIGHLIGHTS• A two-phase coaxial electrospray was designed to produce paclitaxel-loaded fake blood cell Eudragit particles (Eu-FBCP/PTX).• The chemo-immunotherapeutic efficacy was further enhanced after combining with anti-programmed death-ligand 1 antibodies (Eu-FBCP/PTX + aPL).ABSTRACT Because of enhanced efficacy and lower side effects, cancer immunotherapies have recently been extensively investigated in clinical trials to overcome the limitations of conventional cancer monotherapies. Although engineering attempts have been made to build nanosystems even including stimulus nanomaterials for the efficient delivery of antigens, adjuvants, or anticancer drugs to improve immunogenic cancer cell death, this requires huge R&D efforts and investment for clinically relevant findings to be approved for translation of the nanosystems. To this end, in this study, an air-liquid two-phase electrospray was developed for stable bubble pressing under a balance between mechanical and electrical parameters of the spray to continuously produce biomimetic nanosystems consisting of only clinically relevant compounds [paclitaxel-loaded fake blood cell Eudragit particle (Eu-FBCP/PTX)] to provide a conceptual leap for the timely development of translatable chemo-immunotherapeutic nanosystems. This was pursued as the efficacy of systems for delivering anticancer agents that has been mainly influenced by nanosystem shape because of its relevance to transporting behavior to organs, blood circulation, and cell-membrane interactions. The resulting Eu-FBCP/PTX nanosystems exhibiting phagocytic and micropinocytic uptake behaviors can confer better efficacy in chemo-immunotherapeutics in the absence and presence of anti-PD-L1 antibodies than similar sized PTX-loaded spherical Eu particles (Eu-s/PTX).

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