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

ABSTRACT

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.