Chylomicron-biomimetic nanoparticles promote intestinal lymphatic transport by fast fusion with chylomicrons

Intestinal lymphatic transport (ILT) represents a promising pathway for the oral absorption of macromolecular drugs, but the formation of lipid droplet is a rate-limiting step during ILT. In this study, we developed a chylomicron (CM)-biomimetic nanoparticle constructed from CM components, characterized by high lipoprotein affinity, to enable efficient oral delivery of the anti-fibrotic protein klotho via ILT. This approach demonstrated potent therapeutic efficacy in the treatment of renal fibrosis. The nanoparticle exhibited size stability and retained 78.3% enzyme activity after 12 hours of incubation in simulated digestive fluid, while facilitating rapid diffusion through the mucus layer. Within enterocytes, the nanoparticle underwent a CM-like transcytosis process and showed a preference for ILT, as evidenced by cannulation into the main mesenteric lymphatic duct in rats. Notably, this biocompatible oral nanoparticle achieved an absolute bioavailability of 2.7%, delivering superior anti-fibrotic activity in a mouse disease model compared to a 125-fold higher dose of intraperitoneally administered captopril, a first-line anti-fibrotic drug. Our innovative nanoparticle design based on high lipoprotein affinity enables enhanced oral absorption of macromolecular drugs via ILT.