Recent progress in drug discovery has enabled the targeting of specific intracellular molecules to achieve therapeutic effects. These next-generation therapeutics are often biologics that cannot enter cells by mere diffusion. Therefore, it is imperative that drug carriers are efficiently internalized by cells and reach specific target organelles before releasing their cargo. Nanoscale polymeric carriers are particularly suitable for such intracellular delivery. Although size and surface charge have been the most studied parameters for nanocarriers, it is now well appreciated that other properties, for example, particle shape, elasticity and surface composition, also play a critical role in their transport across physiological barriers. It is proposed that a multivariate design space that considers the interdependence of particle geometry with its mechanical and surface properties must be optimized to formulate drug nanocarriers for effective accumulation at target sites and efficient intracellular delivery.