Biological delivery remains a major challenge in biotechnology, partly because it is often not enough to overcome a single delivery barrier. It is highly desirable, yet rarely available, to design delivery carriers with both simple structures and the ability to cross multiple delivery barriers with high efficiency. Herein, we describe a distinct design (dubbed 'SDot') of delivery carriers with a single structural feature that can enhance the crossing of multiple delivery barriers. The bio-interface (the interface with a biological environment) of an SDot nanoparticle is highly hydrophobic, thus enhancing its interactions with lipid membranes, which are the primary components of many bio-delivery barriers. We used quantum dots (QDs) as the model core material of SDots and conjugated them with a RGD peptide. Thus-formed SDots-RGD demonstrated greatly improved abilities of cellular uptake and transcytosis in a brain tumor cell line, U87MG, compared with the conventional nanoparticle counterpart with a hydrophilic bio-interface (wQDs-RGD). Further, after loading a microtubule-binding anticancer drug, paclitaxel (PTX), onto the nanoparticle surface of SDots-RGD, the resulting drug formulation PTX@SDots-RGD displayed excellent ability of intracellular targeting to microtubules in U87MG cells. In a small animal cancer model, PTX@SDots-RGD exhibited significantly higher ability to slow down brain tumor growth than that of PTX@wQDs-RGD and free PTX. Taken together, these experimental results indicated the significant potential of SDots-RGD for bio-delivery, although the possible long-term toxicity of QDs used as the core material needs to be addressed in future work by replacing QDs with clinically approved materials.