Enhanced passive diffusion is usually considered to be the primary cause of the enhanced cellular uptake of cyclometalated drugs because cyclometalation lowers the charge of a metal complex and increases its lipophilicity. However, in this work, monocationic cyclometalated palladium complexes [1] OAc ((NNCN)-N-boolean AND-C-boolean AND-N-boolean AND) and [2]OAc ((NNNC)-N-boolean AND-N-boolean AND-C-boolean AND) were found to self-assemble, in aqueous solutions, into soluble supramolecular nanorods, while their tetrapyridyl bicationic analogue [3] (OAc)(2) ((NNNN)-N-boolean AND-N-boolean AND-N-boolean AND) dissolved as isolated molecules. These nanorods formed via metallophilic Pd center dot center dot center dot Pd interaction and pi-pi stacking and were stabilized in the cell medium by serum proteins, in the absence of which the nanorods precipitated. In cell cultures, these protein-stabilized self-assembled nanorods were responsible for the improved cellular uptake of the cyclometalated compounds, which took place via endocytosis (i.e., an active uptake pathway). In addition to triggering self-assembly, cyclometalation in [1]OAc also led to dramatically enhanced photodynamic properties under blue light irradiation. These combined penetration and photodynamic properties were observed in multicellular tumor spheroids and in a mice tumor xenograft, demonstrating that protein-stabilized nanoaggregation of cyclometalated drugs such as [1]OAc also allows efficient cellular uptake in 3D tumor models. Overall, serum proteins appear to be a major element in drug design because they strongly influence the size and bioavailability of supramolecular drug aggregates and hence their efficacy in vitro and in vivo.