Programmed oral delivery of peptide therapeutics for multiorgan targeting in metabolic disorders of hyperglycemia and hyperuricemia.

Systemic metabolic disorders such as diabetes and hyperuricemia demand multiorgan therapeutic intervention, yet single-target therapies often fail to restore homeostasis. Here, we present an orally administered, multistage-targeted nanoplatform (P1P2NPs) for the sequential delivery of therapeutic peptides to distinct organs. P1P2NPs is composed of a bioresponsive polymer poly(β-amino ester)-disulfide bond-poly(carboxybetaine) (PAE-SS-PCB), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-block poly(carboxybetaine) (DSPE-PCB) and Eudragit L100-55, designed to release peptide P2 (Val-Pro-Tyr-Pro-Gln) in the intestine for dipeptidyl peptidase-IV (DPP-IV) inhibition, while hepatic-targeted peptide P1(Pro-Pro-Lys-Asn-Trp) is selectively liberated in the liver to suppress xanthine oxidase (XOD). Fabricated through sequential emulsification and layer-by-layer assembly, P1P2NPs exhibit spatiotemporal control over drug release, enabling precise modulation of intestinal and hepatic metabolic pathways. In a murine model of diabetic-hyperuricemia comorbidity, the nanoplatform demonstrated synergistic efficacy by normalizing glucose and uric acid levels through multiorgan targeting. This work establishes a paradigm for spatially controlled peptide delivery, offering a versatile strategy for treating complex metabolic diseases.