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

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.