Avatar: The Way of Complex In Vitro Models in Cancer Nanomedicine

ABSTRACT Drug delivery to solid tumors remains a formidable challenge in oncology, despite the promise nanotechnology holds in overcoming the barriers of conventional medicine. However, its limited clinical translation, evidenced by the approval of only around 17 nanomedicines for cancer to date, underscores a critical need to rethink how we evaluate these next‐generation therapeutics. Complex In Vitro Models (CIVMs), including 3D co‐culture models such as spheroids, organoids, organ‐on‐chips, and 3D bioprinted tissues, are already reshaping the oncology landscape by offering physiologically relevant, human‐centric tumor models. Beyond their role in non‐clinical research, CIVMs are increasingly being integrated into clinical practice as real‐time human avatars of disease. As these technologies continue to evolve rapidly, their application in nanomedicine is expanding and must be scaled to meet translational demands. This study critically examines the limitations of conventional cancer models and provides a comprehensive analysis of the strengths, opportunities, and challenges associated with various CIVMs in the context of nanomedicine. We map where each model is most effectively applied and explore the potential for categorizing CIVMs based on their specific context of use. A nuanced understanding of these dimensions will support informed model selection, streamline non‐clinical development, and ultimately enhance translational outcomes in cancer therapeutics.