Simple SummaryMany cancer therapeutics may have a robust effect on target molecules but lack the means of effective localization into tumor cells, thus displaying reduced therapeutic efficacy. Viruses bear naturally evolved machinery to ensure entry and localization of nucleic acid cargo into a cell. Utilizing and better understanding the mechanism of the penton base protein that contributes to the adenovirus cell entry machinery may improve the intracellular delivery of tumor targeting therapeutics. This review describes the progression of penton-base-derived cancer nanotherapeutic development and highlights essential requirements for robust delivery into a tumor cell.AbstractMacromolecular therapeutics such as nucleic acids, peptides, and proteins have the potential to overcome treatment barriers for cancer. For example, nucleic acid or peptide biologics may offer an alternative strategy for attacking otherwise undruggable therapeutic targets such as transcription factors and similar oncologic drivers. Delivery of biological therapeutics into tumor cells requires a robust system of cell penetration to access therapeutic targets within the cell interior. A highly effective means of accomplishing this may be borrowed from cell-penetrating pathogens such as viruses. In particular, the cell entry function of the adenovirus penton base capsid protein has been effective at penetrating tumor cells for the intracellular deposition of macromolecular therapies and membrane-impermeable drugs. Here, we provide an overview describing the evolution of tumor-targeted penton-base-derived nano-capsids as a framework for discussing the requirements for overcoming key barriers to macromolecular delivery. The development and pre-clinical testing of these proteins for therapeutic delivery has begun to also uncover the elusive mechanism underlying the membrane-penetrating function of the penton base. An understanding of this mechanism may unlock the potential for macromolecular therapeutics to be effectively delivered into cancer cells and to provide a treatment option for tumors resisting current clinical therapies.