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The kidney is a major target for drug-induced toxicity, and the renal proximal tubule is frequently affected. Nephrotoxicity is typically detected only late during drug development, and the nephrotoxic potential of newly approved drugs is often underestimated. A central problem is the lack of preclinical models with high predictivity. Validated in vitro models for the prediction of nephrotoxicity are not available. Major problems are related to the identification of appropriate cell models and end points. As drug-induced kidney injury is associated with inflammatory reactions, we explored the expression of inflammatory markers as end point for renal in vitro models. In parallel, we developed a new cell model. Here, we combined these approaches and developed an in vitro model with embryonic stem-cell-derived human renal proximal tubular-like cells that uses the expression of interleukin (IL)-6 and IL-8 as end points. The predictivity of the model was evaluated with 41 well-characterized compounds. The results revealed that the model predicts proximal tubular toxicity in humans with high accuracy. In contrast, the predictivity was low when well-established standard in vitro assays were used. Together, the results show that high predictivity can be obtained with in vitro models employing pluripotent stem cell-derived human renal proximal tubular-like cells.

The rise of antimicrobial resistance is at the forefront of global healthcare challenges, with antimicrobial infections on track to overtake cancer as a leading cause of death by 2050. The high effectiveness of antimicrobial enzymes used in combination with the protective, inert nature of polymer materials represents a highly novel approach toward tackling microbial infections. Herein, we have developed biohybrid glucose oxidase-loaded semipermeable polymersome nanoreactors, formed using polymerization-induced self-assembly, and demonstrate for the first time their ability to “switch on” their antimicrobial activity in response to glucose, a ubiquitous environmental stimulus. Using colony-counting assays, it was demonstrated that the nanoreactors facilitate up to a seven-log reduction in bacterial growth at high glucose concentrations against a range of Gram-negative and Gram-positive bacterial pathogens, including a methicillin-resistant Staphylococcus aureus clinical isolate. After demonstrating the antimicrobial properties of these materials, their toxicity against human fibroblasts was assessed and the dosage of the nanoreactors further optimized for use as nontoxic agents against Gram-positive bacteria under physiological blood glucose concentrations. It is envisaged that such biohybrid nanomaterials will become an important new class of antimicrobial biomaterials for the treatment of bacterial infections.