Programmed Gut–Liver‐Targeted Oral Delivery of Peptide‐Probiotic Nano‐Microsystem for Metabolic Complications of Hyperglycemia and Hyperuricemia

Hyperglycemia and hyperuricemia are highly prevalent metabolic comorbidities characterized by systemic metabolic disturbances and complex multi-organ pathogenesis, urgently requiring synergistic multi-organ-targeted therapeutic strategies. Here, we present a programmed gut-liver-targeted oral peptide-probiotic nano-microsystem for metabolic complications of hyperglycemia and hyperuricemia treatment. The xanthine oxidase (XOD)-inhibitory peptide PPKNW (P1) was loaded in a layer-by-layer reactive oxygen species (ROS)-responsive nanoparticle (P1NPs), followed by engineering on the surface of probiotic Akkermansia muciniphila (Akk), resulting in a peptide-probiotic nano-microsystem (P1NPs@Akk). After oral administration, P1NPs@Akk remained stable during gastric passage. Upon reaching intestinal environment, CS and HA layers were progressively removed, exposing the P1-loaded polymersomes, which were transported across the intestinal epithelium via PAT-1-mediated transcytosis. In the liver, P1 was released in response to ROS-mediated disulfide bond cleavage to inhibit XOD and reduce uric acid synthesis. Meanwhile, Akk was delivered to and colonized in the intestine to regulate glucose metabolism. In a mouse model of combined hyperglycemia and hyperuricemia, P1NPs@Akk promoted hepatic accumulation of P1 and intestinal enrichment of Akk, resulting in significant reductions in blood glucose and uric acid levels. This work presents a programmed gut-liver-targeted oral platform that integrates peptide therapy and probiotic intervention for multi-organ regulation of metabolic disorders.