Surface charge behavior of mezalazine-loaded chitosan-alginate nanoparticles in a 3D multi-layered intestinal in vitro model.

Inflammatory bowel diseases (IBD) are chronic conditions characterized by inflammation in the gastrointestinal tract (GIT), primarily the colon, requiring targeted and effective drug delivery systems to address the limitations of traditional therapies. Mesalazine (MLZ), although commonly used, has low solubility and permeability, limiting its accumulation at sites of inflammation. This study demonstrates that the polymer composition and surface charge of nanoparticles (NPs) can influence transport, mucoadhesion, and cellular interaction in a physiologically relevant environment. MLZ-loaded cationic and anionic NPs were prepared using chitosan (CS) and sodium alginate (SA), then characterized by particle size, zeta potential (ZP), morphology, and thermal properties. MLZ-loaded NPs were tested in a 3D multilayer in vitro model of intestinal inflammation, including epithelial, stromal, and endothelial cells. The NPs exhibited size of 277 to 410 nm, PdI lower than 0.5, ZP of +38 mV to -30 mV, colloidal stability, and spherical morphology. NPs rich in SA 1:4:1.25 (CS:SA:MLZ) exhibited higher permeability and faster diffusion, as well as weaker cellular interactions with mucin compared to NPs rich in CS 4:1:1.25 (CS:SA:MLZ), which exhibited greater mucoadhesion, stronger cell-surface interactions, and longer apical retention, suggesting potential for the treatment of localized conditions such as IBD. Both formulations significantly reduced proinflammatory cytokine levels, indicating their promise for improved management of inflammation. These nanotechnological strategies highlight how surface charge characteristics and polymer concentration affect nanoparticle transport and biointeraction in complex in vitro platforms, providing valuable insights for the development of nanosystems for possible rectal administration.