The unique microenvironment of tumors, such as dense extracellular matrix, elevated interstitial pressure, and high cell packing density, makes it difficult for drugs to penetrate deep into the tumor tissue, resulting in insufficient drug concentration in the inner regions of the tumor and the inability to completely eradicate all tumor cells. Although concentration driven passive diffusion and receptor-mediated endocytosis-based active penetration have partially addressed the aforementioned issues, any single treatment strategy inevitably has certain limitations. In this regard, our research group has developed a three-metal supramolecular drug complex (Cπ-TMSDC) that combines both passive diffusion and active penetration mechanisms by utilizing the cation-π bridging effect (Figure 1a). This complex formes through the cation-π interaction between two drug monomers. Subsequently, the obtained Cπ-TMSDC can further self-assemble into cation-π-based three-metal supramolecular drug micelles (Cπ-TMSDM). Within the acidic microenvironment of tumor tissues, the cation-π interaction in Cπ-TMSDM initially dissociates, leading to the rapid release of Pt-COOK. Under the influence of a concentration gradient-driven passive diffusion mechanism, platinum drugs rapidly infiltrate the outer cells of the tumor tissue (Figure 1b). Meanwhile, the released Ru-Cur undergoes secondary self-assembly, forming positively charged small micelles that induce receptor-mediated endocytosis. This enables active penetration into the inner solid tumors (Figure 1b). The aforementioned strategies have realized effective penetration of supramolecular drugs into the deep layers of tumors, leading to highly efficient tumor treatment.

The relevant research findings have been published online in "Advanced Functional Materials."

(Paper link: https://onlinelibrary.wiley.com/doi/10.1002/adfm.202205043).

Doctoral candidate Chengfei Liu from the research group is the first author of the paper, while Associate Professor Li Fan and Professor Wei Tian from the Air Force Medical University are the corresponding authors.