Engineering mucus-penetrating and enzyme-responsive nanostructured carriers for precision targeting of curcumin's pharmacokinetics and colitis-alleviating pathways

The development of advanced delivery systems that precisely control the absorption, metabolism, and therapeutic efficacy of bioactive compounds is a burgeoning area in nanomedicine. This study introduced an innovative strategy for modulating the pharmacokinetics and therapeutic pathways of curcumin through engineered mucus-penetrating nanostructured lipid carriers (CUR-NLC) and colon-targeted microparticles (CUR-MC). These nanocarriers are designed with hierarchical structures and enzyme-responsive materials to achieve site-specific drug delivery. CUR-NLCs demonstrated superior adhesion and penetration through the ileal mucosa, facilitating curcumin metabolism via host enzymes, while CUR-MCs enhanced colonic targeting, enabling enzyme-responsive curcumin release at inflamed lesion and promoting microbiota-mediated metabolism. In this vein, CUR-NLC achieved the highest peak concentration C_max(CUR) and absorption rate (K_a) for curcumin, while CUR-MC improved hepatoenteral circulation and optimized the oral bioavailability and plasma concentrations of its active metabolite tetrahydrocurcumin (THC). Western-blot analysis revealed that CUR-NLC facilitated anti-colitis effect by suppressing inflammatory response through the NF-κB/TLR₄ pathway. Furthermore, our research uncovered a positive correlation between the mucoadhesive efficiency of nanocarriers and their cellular uptake by macrophages. Notably, CUR-MCs demonstrated an increase in colon mucoadhesive capacity (18.35 folds) and macrophage internalization efficiency (28.74 folds) at the colonic mucosa, triggering a superior restoration effect on colonic mucosal inflammation. CUR-MC mitigated colitis by repairing the epithelial physical barrier and enhancing colonic mucosal immunity through the promotion of goblet cell proliferation and the production of occludin and mucin 2. This work highlights the potential of precisely engineered nanostructured carriers in facilitating drug adhesion and permeability efficiency across intestinal mucosa, extending pharmacokinetics of host-microbiome mediated metabolism and enhancing therapeutic efficacy, contributing to the development of site-specific drug delivery techniques in nanomedicine.