Chitosan–astaxanthin nanoparticles (CS–ASTNPs) exhibited an anti-colitis activity, but their poor mobility restricts anti-inflammatory efficacy. Chlamydomonas reinhardtii (C. reinhardtii) was employed to load CS–ASTNPs to construct astaxanthin-loaded microalgal motors (CS–AST@CR). The particle size of CS–AST@CR was 4.2 ± 0.21 μm and its swimming speed was 89.3 ± 4.4 µm/s, which was slower than native C. reinhardtii (117.2 ± 2.7 µm/s), though their movement trajectories remained comparable. Compared to CS–ASTNPs, CS–AST@CR notably alleviated chronic colitis symptoms. It enhanced colon barrier function by promoting ZO-1, occludin, and MUC2 expression. Furthermore, CS–AST@CR markedly reduced TNF-α, IL-1β, and NLRP3 inflammasome production while increasing IL-10 levels. The oxidative response was effectively suppressed via activating the Nrf2/HO-1 pathway. Additionally, CS–AST@CR significantly increased Lactobacillus and Enterorhabdus abundance; whereas, CS–ASTNPs elevated Akkermansia and Bifidobacteriaceae richness. Collectively, CS–AST@CR integrated the advantages of microalgal motility and nanoparticle functionality, showing great potential for development as functional foods or therapeutic agents for colitis treatment.
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