Orally delivered P1P2NPs nanoplatform normalizes glucose and uric acid in diabetic-hyperuricemia murine model.

Diabetes and hyperuricemia are prevalent metabolic disorders often co-occurring, demanding complex, multiorgan therapeutic strategies. Current single-target treatments frequently fall short in restoring systemic metabolic homeostasis, leaving a critical gap for integrated interventions. Oral peptide delivery, despite its patient convenience, faces significant hurdles like gastric degradation, enzymatic breakdown, and poor intestinal absorption, severely limiting the therapeutic potential of many promising peptide candidates. This study addresses these challenges by developing a novel oral delivery system for peptides targeting multiple organs and pathways simultaneously.

Researchers engineered P1P2NPs, an orally administered, multistage-targeted nanoplatform, for sequential peptide delivery to distinct organs. The system 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. It was 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) was selectively liberated in the liver to suppress xanthine oxidase (XOD). The nanoplatform was fabricated through sequential emulsification and layer-by-layer assembly. Efficacy was evaluated in a murine model of diabetic-hyperuricemia comorbidity.

In the murine model of diabetic-hyperuricemia comorbidity, the P1P2NPs nanoplatform demonstrated significant synergistic efficacy.

The programmed oral delivery system successfully normalized both glucose and uric acid levels, indicating effective multiorgan targeting. This dual action was achieved through the spatiotemporal control of peptide release: P2 inhibited DPP-IV in the intestine, contributing to glucose regulation, while P1 suppressed XOD in the liver, directly addressing hyperuricemia. The precise modulation of intestinal and hepatic metabolic pathways highlights the platform's ability to overcome the limitations of single-target therapies and restore metabolic homeostasis. While specific quantitative data like percentages or p-values were not detailed in the abstract, the qualitative outcome of "normalized" levels suggests a robust and clinically meaningful therapeutic effect in this preclinical model.