Clinical translation of nanoparticle-based drug delivery systems is hindered by an array of challenges including poor circulation time and limited targeting. Novel approaches including designing multifunctional particles, cell-mediated delivery systems, and fabrications of protein-based nanoparticles have gained attention to provide new perspectives to current drug delivery obstacles in the interdisciplinary field of nanomedicine. Collectively, these nanoparticle devices are currently being investigated for applications spanning from drug delivery and cancer therapy to medical imaging and immunotherapy. Here, we review the current state of the field, highlight opportunities, identify challenges, and present the future directions of the next generation of multifunctional nanoparticle drug delivery platforms. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.