The concept of achieving Paul Erhlich's inspired vision of a "magic bullet" to treat disease is now materializing with select monoclonal antibody therapies, but this achievement is not well replicated by current nanomedicine clinical candidates. Nanomedicine technologies have often proven unstable in vivo due to premature release of drug cargoes during circulation resulting in low therapeutic delivery to targeted cells. Compounding this nanoparticle payloads that reach target cells are typically internalized within endosomes, contributing to further drug loss and diminished intracellular drug bioavailability. Historically, size limited extravasation of nanoparticles beyond the circulation followed by inhomogeneous and inadequate deep penetration into disease sites has been the major nanoparticle biological barrier. However, nanomedicines can function as excipients and prolonged release systems to favorably alter drug pharmacokinetics and volume of distributions for greater efficacy and lower toxicity. Sn2 phospholipid prodrugs in conjunction with a contact-facilitated drug delivery mechanism have been found to minimize premature drug diffusional loss during circulation and to increase target cell bioavailability. The Sn2 phospholipid prodrug approach has been applied equally well for vascular constrained lipid-encapsulated particles delivering anti-Angiogenic therapies, such as fumagillin or docetaxel, and to micelles penetrating through inflamed endothelium into disseminated cancers, such as in multiple myeloma with anti-cMYC payloads. Innovations like Sn2 phospholipid prodrugs in combination with the contact-facilitated drug delivery mechanism are poised to contribute to the translational success of nanomedicines by increasing efficacy and safety for an array of poorly treated diseases.