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Engineered nanomaterials (ENMs) as adjuvants can potentiate the adaptive immune responses to antigens by activating immune cells in three dimensional (3D) matrixes of tissues. However, few reports explored the interactions of nano-adjuvants and immune cells at 3D nano-bio interfaces. Herein we designed an alginate-calcium microsphere of macrophage cells to explore the interactions. By an extensive comparison of ENM-induced cytokines in 2D and 3D cultured cells, IL-1β released in 3D microspheres was found to be a predictive biomarker to assess ENM-induced immune responses in vivo. Among nine representative ENMs, La 2 O 3 boosts the highest adaptive humoral immune response, even stronger than clinically used Alum adjuvant. It could be attributed to the biotransformation of La 2 O 3 from spherical particles into urchin-like LaPO 4 , resulting in strong biopersistence and NLRP3 inflammasome activation. These findings could be potentially used for the high throughput screening of nano-adjuvants from increasingly invented ENMs to speed up their clinical uses. Cellular internalized La 2 O 3 nanoparticles are able to transform into "sea urchin" structures in macrophages encapsulated in 3D microtissues. This unique biotransformation elicits NLRP3 inflammasome activation, bursts massive IL-1β release and results in prolonged retention of nanoparticles in 3D biological matrixes, which induce substantial adjuvant effects in animals. The IL-1β production could therefore be used to predict the immune responses of engineered nanomaterials for rapid nano-adjuvant screening. Unlabelled Image [ABSTRACT FROM AUTHOR]

Exploration of medical radiation countermeasures (MRCs) has great implications in protection of mammals from radiation damages. While flagellin has been recently reported to show radioprotective effects, the relationships between flagellin structure and radioprotective activity are rarely explored. Herein, we deliberately edited the amino acid sequence of flagellin in its binding domain with toll-like receptor 5 (TLR5) for exploration of potent flagellin derivatives (Fds). An in vitro screening paradigm was developed to examine the radioprotective effects of six engineered Fds. Notably, mutation of 103 threonine on flagellin into asparagine resulted in a potent MRC candidate (Fd-T103N) displaying 1.28-fold increment of interactions with TLR5. Fd-T103N was able to further activate NF-κB pathway, induce immune protective cytokine (e.g. G-CSF) release, and significantly ameliorate γ-irradiation induced cell death. The protection effects of Fd-T103N were further validated in mice exposed to 10 Gy γ-irradiations. Compared to parent flagellin, Fd-T103N treatment showed higher G-CSF release in mouse blood, lower intestine damages, and 13% increments of mouse survival rates. In short, the established predictive paradigm could greatly reduce the labor-, time- and animal-costs in exploration of MRC candidates. Fd-T103N is a promising candidate of investigational new drug for radioprotection. [ABSTRACT FROM AUTHOR]