The invention provides multifunctional supramolecular self-assembled nanoparticles (SSNPs) comprising a set of rationally designed components that collectively facilitate efficient intestinal absorption of siRNA. The nanoparticles can induce potent TNF-α silencing in macrophages. Single gavage of SSNPs in mice depleted systemic TNF-α production at an siRNA dose as low as 50 μg/kg, and protected the mice from lipopolysaccharide-induced hepatic injury.