Although nanoparticles (NPs) have been used for many drug delivery applications, oral absorption of NPs has remained a big challenge. NPs for oral delivery of biotherapeutics have to penetrate both the diffusion barrier of the mucus and the absorption barrier of the epithelium. This creates an obstacle for developing an effective NP platform for oral delivery because overcoming these two barriers requires different or even contradictory surface properties. Inspired by the features of some viruses, this study reports the development of a unique sub-50 nm polymeric NP platform that possesses a large amount of targeting ligands anchored on the surface while being moderately concealed under a "muco-inert" shield. NP library screening demonstrates a strong correlation between the relative lengths of the surface components and NP behavior on mucosal tissue. When a balance is obtained regarding optimal shielding of ligands, the NPs exhibit both excellent mucus permeation and transepithelial transport, and are efficiently absorbed into systemic circulation. Insulin-loaded NPs as a model oral therapy for diabetes generates a hypoglycemic response on diabetic animals following oral administration. This study demonstrates the great potency of a NP platform that exhibits an affinity balance between mucus and epithelium in facilitating the oral delivery of biotherapeutics.