Intestinal Macrophage-Mediated Exosomal Repackaging Establishes Bioactive Reservoirs for Long-Acting Oral Peptide Therapy.

Oral peptide delivery systems are conventionally engineered to improve intestinal absorption, but they rarely address the progressive and systemic nature of chronic inflammatory disorders such as type-2 diabetes (T2D), which requires both durable glycemic control and immunometabolic management. Here, we report an oral delivery system based on porous calcium carbonate/sodium alginate (PCC/SA) microparticles loaded with exenatide-chitosan oligosaccharide (EXE-COS). The PCC/SA carrier facilitates the efficient intestinal absorption and transepithelial transport of EXE-COS. Notably, in the lamina propria, EXE-COS can be selectively internalized by intestinal macrophages (ITMs) in vivo, driving their polarization toward anti-inflammatory M2-phenotypes. These M2-macrophages enable endogenous repackaging of exenatide into exosomes through orchestrated modulation of exosome biogenesis and trafficking. Through gut-organ axes, exosomes target diabetes-associated inflamed metabolic sites (pancreas, liver, and adipose tissue), establishing long-lived bioactive reservoirs to precisely restore tissue homeostasis and sustain glycemic control. Critically, a single oral dose of EXE-COS@PCC/SA achieved up to 8 day hypoglycemic effects in db/db mice following long-term administration, while concurrently improving systemic inflammation, lipid metabolism, and insulin resistance. This intestinal macrophage-mediated in situ exosomal biogenesis and endogenous drug repackaging represents a versatile long-acting oral peptide platform, showing promise for durable and safe management of T2D and other chronic inflammatory diseases.