Nanoparticle morphology (size, shape, and composition) and surface chemistry are the determining factors underpinning the efficacy of such materials in therapeutic applications. The size, shape, and surface chemistry of a nanoparticle can strongly influence key properties such as interactions with diverse biological fluids and interfaces and, in turn, impact the delivery of bioactive cargo, modulating therapeutic performance. This is exemplified in ocular drug delivery, where potential therapeutics must navigate complex biological media such as the gel-like vitreal fluid and the retina. Biodegradable block copolymer amphiphiles are a robust tool for the engineering of various types of self-assembled nanoparticles with diverse morphologies ranging from spherical and tubular polymersomes to spherical and worm-like micelles. Here, we explore the effect of morphological features such as shape and surface chemistry upon the interactions of a series of copolymer nanoparticles with retinal (ARPE-19) cells and the release of a low solubility drug (dexamethasone) that is currently used in ocular therapy and study their diffusion in vitreous using ex vivo eyes. We demonstrate that both aspect ratio and surface chemistry of nanoparticles will influence their performance in terms of cell uptake, drug release, and diffusion with high aspect ratio shapes demonstrating enhanced properties in relation to their spherical counterparts.