Chylomicron-biomimetic nanoparticles enable efficient intestinal lymphatic transport for oral delivery of therapeutic proteins

Oral delivery of therapeutic proteins remains a major challenge due to poor gastrointestinal stability and limited transport across the intestinal epithelium. Intestinal lymphatic transport (ILT), a physiological pathway responsible for lipid absorption via chylomicron (CM) assembly, offers a promising route to overcome these barriers, yet its efficient exploitation for macromolecular delivery remains elusive. Here, we report chylomicron-biomimetic nanoparticles (CMB-NPs) designed to engage endogenous CM assembly and transport pathways, thereby facilitating ILT-mediated transcytosis. The nanoparticles exhibit high lipoprotein affinity and strong association with CMs. Mechanistic studies reveal endoplasmic reticulum/Golgi-associated trafficking, ApoB-48-associated processing, and transport into mesenteric lymphatics in vivo, collectively supporting their engagement with endogenous CM-associated transport pathways. As a result, the system achieves an absolute oral bioavailability of 26.7% for the model protein Klotho, markedly enhancing systemic exposure and promoting preferential accumulation in fibrotic kidneys. In murine models of renal fibrosis, oral administration of Klotho-loaded CMB-NPs significantly alleviated disease progression and produced robust anti-fibrotic effects by restoring renal function and suppressing fibrotic signaling. Collectively, this work establishes engagement with endogenous CM-associated transport pathways as an effective strategy for oral protein delivery and provides a generalizable framework for exploiting ILT in nanomedicine.