Nanoparticles (NPs) are the focus of research efforts that aim to develop successful drug delivery systems for the brain. Polypeptide nanocarriers are versatile platforms and combine high functionality with good biocompatibility and biodegradability. The key to the efficient brain delivery of NPs is the specific targeting of cerebral endothelial cells that form the blood–brain barrier (BBB). We have previously discovered that the combination of two different ligands of BBB nutrient transporters, alanine and glutathione, increases the permeability of vesicular NPs across the BBB. Our aim here was to investigate whether the combination of these molecules can also promote the efficient transfer of 3-armed poly(l-glutamic acid) NPs across a human endothelial cell and brain pericyte BBB co-culture model. Alanine and glutathione dual-targeted polypeptide NPs showed good cytocompatibility and elevated cellular uptake in a time-dependent and active manner. Targeted NPs had a higher permeability across the BBB model and could subsequently enter midbrain-like organoids derived from healthy and Parkinson’s disease patient-specific stem cells. These results indicate that poly(l-glutamic acid) NPs can be used as nanocarriers for nervous system application and that the right combination of molecules that target cerebral endothelial cells, in this case alanine and glutathione, can facilitate drug delivery to the brain.

We report the feasibility of using gelatin hydrogel networks as the host for the in situ, environmentally friendly formation of well-dispersed zinc oxide nanoparticles (ZnONPs) and the evaluation of the antibacterial activity of the as-prepared composite hydrogels. The resulting composite hydrogels displayed remarkable biocompatibility and antibacterial activity as compared to those in previous studies, primarily attributed to the uniform distribution of the ZnONPs with sizes smaller than 15 nm within the hydrogel network. In addition, the composite hydrogels exhibited better thermal stability and mechanical properties as well as lower swelling ratios compared to the unloaded counterpart, which could be attributed to the non-covalent interactions between the in situ formed ZnONPs and polypeptide chains. The presence of ZnONPs contributed to the disruption of bacterial cell membranes, the alteration of DNA molecules, and the subsequent release of reactive oxygen species within the bacterial cells. This chain of events culminated in bacterial cell lysis and DNA fragmentation. This research underscores the potential benefits of incorporating antibacterial agents into hydrogels and highlights the significance of preparing antimicrobial agents within gel networks.