Nanoarmored Probiotic for Inflammatory Bowel Disease Bacteriotherapy via a Dual-Targeting Host-Microbiota Reprogramming

Inflammatory bowel disease (IBD) involves oxidative stress, chronic inflammation, and gut microbiota dysbiosis, complicating therapeutic intervention. Herein, we engineer a robust living therapeutic platform via a biomimetic nanoarmoring strategy. A uniform FDA-approved calcium carbonate (CaCO 3 ) nanocoating is in situ mineralized on the surface of the probiotic Escherichia coli Nissle 1917 (EcN) preassembled with the flavonoid luteolin (Lut), creating the nanocomposite EcN-Lut/CaCO 3 . This nanoarmoring strategy enhances bacterial viability under simulated gastrointestinal conditions (a 100-fold survival increase) and enables colon-specific delivery. The composite demonstrates potent reactive oxygen species scavenging (∼100%) and immunomodulatory capacity in vitro, downregulating pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-17A) while elevating anti-inflammatory IL-10. In a DSS-induced murine colitis model, EcN-Lut/CaCO 3 significantly attenuated disease severity, restoring colon length (a 57.30% recovery compared to healthy control), reducing the disease activity index by 72.73% relative to the DSS group, and improving histopathology. Transcriptomic analysis reveals dual regulation of host signaling pathways with activation of cAMP/cGMP-PKG metabolic cascades and suppression of IL-17/TNF inflammatory pathways. Concurrently, 16S rRNA sequencing shows that the nanoarmored platform effectively reverses dysbiosis, selectively enriching beneficial genera such as Lactobacillus and Muribaculaceae while suppressing proteobacterial pathobionts. This work presents a generalizable nanoarmoring strategy that transforms fragile probiotics into intelligent, multifunctional living therapeutics, offering a powerful approach for the targeted treatment of IBD and other complex inflammatory disorders.