Precision-Architected Drug-Stabilized Cu₅ Clusters Mediate Multimodal Therapeutic Intervention in Colitis

Atomically precise metal clusters, featuring versatile coordination modes, tailorable architectures, and adjustable ligands, demonstrate promising potential as candidates for drug delivery platforms for disease treatment. Herein, an anti-inflammatory agent-stabilized copper cluster was fabricated to alleviate colitis via multimodal therapy. Specifically, propargylated drugs are conjugated to the Cu₅ cluster via μ₃- and μ₅-bridging modes. The resulting Cu₅ cluster exhibited remarkable gastrointestinal stability and antioxidant capability. Integrated with the inherent anti-inflammatory properties of the drug, the cluster following oral administration can efficiently scavenge the reactive oxygen nitrogen species at inflamed colon sites, attenuate the inflammatory response, and potentially repolarize the macrophage, which further promotes the restoration of the intestinal barrier. More importantly, the Cu₅ cluster with a positive surface charge can effectively inhibit pathogenic bacteria while restoring gut microbiota diversity and abundance, significantly alleviating dextran sulfate sodium-induced colitis in mice. This work would establish a paradigm for designing multifunctional metal clusters and offer insights for drug delivery.