Publications

Bacterial infections pose a significant global health challenge aggravated by the rise of antimicrobial resistance (AMR). Among the obstacles preventing effective treatment are biological barriers (BBs) within the body such as the mucus layer. These BBs trap antimicrobials, necessitating higher doses and ultimately accelerating AMR. Addressing this issue requires innovative therapeutic strategies capable of bypassing BBs to deliver drugs more effectively. Here, we present nanomotors (NMs) based on hyaluronic acid (HA)- and urease-nanogels (NGs) as a solution to navigate effectively in viscous media by catalyzing the decomposition of urea into ammonium and carbon dioxide. These HA-based nanomotors (HA-NMs) were loaded with chloramphenicol (CHL) antibiotic and demonstrated superior antimicrobial activity against Escherichia coli(E. coli) compared to mesoporous silica NMs (MSNP-NMs), a reference in the field of NMs. Moreover, using an in vitro transwell model we evaluated the ability of HA-NMs to penetrate mucin barriers, effectively reducing E. coli proliferation, whereas the free antibiotic did not reduce bacteria proliferation. The optical density reduction at 24 h was over ten times greater than with free CHL. These organic-based enzyme-powered NMs represent a significant advancement in drug delivery, offering a promising approach to combat AMR while addressing the challenges of crossing complex BBs.

JTD Keywords: Bacterial infections, Biologicalbarriers, Design, Drug deliver, Enzyme, Mucu, Nanogels, Nanomotors, Nanoparticles

Biological barriers present a significant obstacle to treatment, especially when drugs are administered locally to increase their concentrations at the target site while minimizing unintended off-target effects. Among these barriers, mucus presents a challenge, as it serves as a protective layer in the respiratory, urogenital, and gastrointestinal tracts. Its role is to shield the underlying epithelial cells from pathogens and toxic compounds but also impedes the efficient delivery of drugs. Despite the exploration of mucolytic agents to improve drug delivery, overcoming this protective barrier remains a significant hurdle. In our study, we investigate an alternative approach involving the use of catalase-powered nanobots. We use an in vitro model that simulates intestinal mucus secretion to demonstrate the dual functionality of our nanobots. This includes their ability to disrupt mucus, which we confirmed through in vitro and ex vivo validation, as well as their self-propulsion to overcome the mucus barrier, resulting in a 60-fold increase compared with passive nanoparticles. Therefore, our findings highlight the potential utility of catalase-powered nanobots as carriers for therapeutic agents since they could enhance drug delivery efficiency by penetrating the mucus barrier.

JTD Keywords: Biological barrier, Biological barriers, Drug-delivery, Growth, Hydrogen-peroxide, Muci, Mucus, Nanobots, Nanomedicine, Nanomotors, Transport

The intestinal mucus lines the luminal surface of the intestinal epithelium. This mucus is a dynamic semipermeable barrier and one of the first-line defense mechanisms against the outside environment, protecting the body against chemical, mechanical, or biological external insults. At the same time, the intestinal mucus accommodates the resident microbiota, providing nutrients and attachment sites, and therefore playing an essential role in the host–pathogen interactions and gut homeostasis. Underneath this mucus layer, the intestinal epithelium is organized into finger-like protrusions called villi and invaginations called crypts. This characteristic 3D architecture is known to influence the epithelial cell differentiation and function. However, when modelling in vitro the intestinal host–pathogen interactions, these two essential features, the intestinal mucus and the 3D topography are often not represented, thus limiting the relevance of the models. Here we present an in vitro model that mimics the small intestinal mucosa and its interactions with intestinal pathogens in a relevant manner, containing the secreted mucus layer and the epithelial barrier in a 3D villus-like hydrogel scaffold. This 3D architecture significantly enhanced the secretion of mucus. In infection with the pathogenic adherent invasive E. coli strain LF82, characteristic of Crohn’s disease, we observed that this secreted mucus promoted the adhesion of the pathogen and at the same time had a protective effect upon its invasion. This pathogenic strain was able to survive inside the epithelial cells and trigger an inflammatory response that was milder when a thick mucus layer was present. Thus, we demonstrated that our model faithfully mimics the key features of the intestinal mucosa necessary to study the interactions with intestinal pathogens.

JTD Keywords: 3d in vitro models, barrier function, bile-salts, cells, drug-delivery, host-pathogen interaction, host–pathogen interaction, hydrogels, ileal mucosa, infection, intestinal models, intestinal mucus, microbiome, patient, responses, 3d in vitro models, Intestinal mucus, Invasive escherichia-coli