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

Abstract

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 (CaCO₃) nanocoating is in situ mineralized on the surface of the probiotic <i>Escherichia coli</i> Nissle 1917 (EcN) preassembled with the flavonoid luteolin (Lut), creating the nanocomposite EcN-Lut/CaCO₃. 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/CaCO₃ 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 <i>Lactobacillus</i> and <i>Muribaculaceae</i> 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.