Self-Assembled Peptide–Lanthanide Nanoclusters for Safe Tumor Therapy: Overcoming and Utilizing Biological Barriers to Peptide Drug Delivery

Developing a sophisticated nanomedicine platform to deliver therapeutics effectively and safely into tumor/cancer cells remains challenging in the field of nanomedicine. In particular, reliable peptide drug delivery systems capable of overcoming biological barriers are still lacking. Here, we developed a simple, rapid, and robust strategy to manufacture nanoclusters of ∼90 nm in diameter that are self-assembled from lanthanide-doped nanoparticles (5 nm), two anticancer peptides with different targets (BIM and PMI), and one cyclic peptide iNGR targeted to cancer cells. The peptide–lanthanide nanoclusters (LDC-PMI-BIM-iNGR) enhanced the resistance of peptide drugs to proteolysis, disassembled in response to reductive conditions that are present in the tumor microenvironment and inhibited cancer cell growth <i>in vitro</i> and <i>in vivo</i>. Notably, LDC-PMI-BIM-iNGR exhibited extremely low systemic toxicity and side effects <i>in vivo</i>. Thus, the peptide–lanthanide nanocluster may serve as an ideal multifunctional platform for safe, targeted, and efficient peptide drug delivery in cancer therapy