M2 macrophage-based biohybrid system regulates intestinal microbiota homeostasis and immunity for the treatment of inflammatory bowel disease.

Abstract

The pathogenesis of inflammatory bowel disease (IBD) involves a self-perpetuating cycle driven by oxidative stress, microbial dysbiosis, and immune dysregulation. Restoring intestinal microbiota homeostasis and immune balance is therefore critical for intestinal health and long-term disease remission. In this study, an M2 macrophage-based biohybrid system (GaInMg@PDA@M2) was constructed to achieve synergistic intervention against these multiple pathological pathways. This biohybrid system utilized M2 macrophages with inherent inflammatory tropism as delivery vehicles, loaded with multifunctional nanoparticles (GaInMg@PDA) composed of liquid metal (GaIn), magnesium ions (Mg²⁺) and polydopamine (PDA). The nanoparticles effectively scavenged reactive oxygen species and exhibited synergistic antibacterial effects with the GaIn component, while the released Mg²⁺ further promoted macrophage polarization towards the anti-inflammatory M2 phenotype. In a DSS-induced murine colitis model, GaInMg@PDA@M2 demonstrated inflammatory targeting for the diseased colonic tissue and significantly ameliorating clinical symptoms including disease activity index, colon shortening and histopathological damage. The therapeutic mechanisms involved downregulation of pro-inflammatory cytokines, upregulation of anti-inflammatory cytokines, enhancement of antioxidant enzyme activity, restoration of intestinal tight-junction protein expression, and rebalancing of gut microbiota homeostasis. This "cell-homing and multi-effect synergy" strategy represented a precise therapeutic approach capable of disrupting the key pathological cycle in IBD. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD) is driven by a self-perpetuating cycle of oxidative stress, microbial dysbiosis, and immune dysregulation, making restoration of intestinal ecosystem balance a major therapeutic challenge. Conventional therapies often lack specificity or fail to address these interconnected pathologies simultaneously, owing to systemic side effects, non-specific immunosuppression, and diminished efficacy over time. In response, a paradigm shift toward a multi-targeted strategy that concurrently tackles oxidative stress, corrects dysbiosis, and resolves inflammation is imperative to break this cycle. To this end, an M2 macrophage-based biohybrid system was developed to achieve synergistic intervention across these key pathological pathways, overcoming the limitations of conventional drugs and enabling simultaneous modulation of multiple core disease mechanisms.