Advances in understanding nanoparticles' interactions with the immune system in the last two decades have shaped not only the way immunotoxicity is analyzed but also the way nanoparticles are designed for therapeutic applications. Current approaches for assessing nanoparticle immunotoxicity rely on a conventional framework established and optimized for various drug product types, including biotechnology therapeutics, small-molecule drugs, and therapeutic nucleic acids. The sophistication offered by nanotechnology drug delivery carriers is often associated with the increased complexity of the physicochemical properties of nanotechnology-based formulations and their behavior in biological systems. Such complexity often creates challenges for preclinical studies and motivates the expansion of the methodological framework to include novel approaches and optimize the existing ones. Herein, I review the experience of the Nanotechnology Characterization Laboratory in analyzing the immunotoxicity of cancer nanotechnology concepts to highlight current and emerging approaches and outline the future direction for the field.