<p>Oral administration is the preferred route for drug delivery, yet its potential is severely limited by the complex biological barriers of the gastrointestinal tract. A common way to address this is through the use of engineered nanoparticles (NPs), which can protect therapeutic cargo and enhance absorption. While there has been tremendous interest in the synthesis and fabrication of NPs, questions about how their fundamental physicochemical properties dictate their success or failure in vivo have only recently received systematic attention. In this review, we outline how an integrated perspective, focused on the key design challenges of intestinal transit, can complement a purely mechanistic view. In particular, we explain how the properties required for a nanoparticle to penetrate the protective mucus layer are often in direct conflict with those required for efficient epithelial cell uptake. To address this, we propose conceptual frameworks for both evaluating and resolving this conflict. This review shows that the rational design of oral nanocarriers is much more than optimizing a single parameter: it is about creating integrated systems that can dynamically navigate the contradictory demands of the gut interface.</p>