Oral Astilbin Nanogels Modulate Senescence‐Associated CD4 + T Cells and Promote T reg Induction in Aged Mice with Colitis

ABSTRACT Inflammatory bowel disease (IBD) in older individuals is characterized by immune senescence and deteriorating intestinal homeostasis, both of which limit the efficacy of current therapies. Here, we develop fluorinated β‐glucan/pectin nanogels (F 2 ‐Ast@NGs) for oral delivery of astilbin, a natural flavonoid with anti‐inflammatory and immunoregulatory activities. This multifunctional platform integrates gastrointestinal protection, colon‐targeted release, and local immune modulation. The β‐glucan shell preserves nanogel stability during upper gastrointestinal transit while enabling β‐glucanase‐responsive disassembly in the colon. Fluorocarbon segments enhance mucus penetration, and the pectin matrix prolongs colonic retention, promoting drug accumulation at inflamed sites. In aged mice with dextran sulfate sodium (DSS)‐induced colitis, F 2 ‐Ast@NGs alleviate disease severity, attenuate senescence‐associated features of colonic CD4 + T cells, and enhance Foxp3 + regulatory T cell (T reg ) responses. Concurrently, the β‐glucan/pectin nanogel matrix contributes to increased short‐chain fatty acid production and favorable alterations in gut microbial composition. Notably, the therapeutic efficacy of F 2 ‐Ast@NGs is markedly attenuated in Foxp3 + T reg ‐depleted mice, supporting an important role for T reg ‐mediated immunoregulation. Collectively, F 2 ‐Ast@NGs enable precise colonic delivery while coordinately remodeling the intestinal immune and microbial microenvironment, providing a promising oral nanotherapeutic strategy for colitis in aged hosts.