An inflammation-responsive therapeutic gel for precise microbiota modulation in colitis

Microbiome dysbiosis is a hallmark of inflammatory bowel disease (IBD), and its reprogramming represents a promising intervention strategy. Existing treatments are often limited by gastrointestinal instability and non-specific microbial toxicity, leading to suboptimal outcomes and potential aggravation of IBD symptoms. Herein, we construct a calcium phosphotungstate gel (CPW), characterized by tortile nanofibers (length > 5 μm, diameter ~ 20 nm) forming a stable 3D network, which remains structurally intact in gastrointestinal fluid for over 24 h and exhibits commendable resistance to gastric acid and digestive enzymes. Furthermore, CPW disintegrates specifically in response to the inflammatory biomarker calprotectin (CAL), releasing over 54% of tungsten payloads within 12 h (versus < 6% without CAL). The locally released tungsten ions selectively inhibit nitrate respiratory enzymes and induce apoptosis in approximately 50% of nitrate-dependent pathogens within 24 h, enabling precise microbiome modulation. As a versatile carrier, CPW demonstrated exceptional protection for diverse therapeutics (DIO, peptides, nucleic acids) against digestive enzymes, enabling > 70% cargo release specifically at inflamed sites. In DSS-induced colitis mice, DEX-loaded CPW (DEX@CPW) significantly improved colon length (comparable to healthy controls), reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α by 2.1-3.3 fold), and restored beneficial microbiota. Crucially, CPW reduced systemic tungsten exposure by 62.7% in kidneys while increasing intestinal tungsten retention by 1.67-fold, demonstrating superior targeting. This dual-function platform-integrating pathogen-selective metallotherapy and inflammation-triggered drug release-represents a promising clinical approach for IBD by simultaneously modulating dysbiosis and ameliorating inflammation.