A Hierarchical Peptide–Lanthanide Framework To Accurately Redress Intracellular Carcinogenic Protein–Protein Interaction

Intracellular protein-protein interactions (PPIs) are a vital and yet underexploited class of therapeutic targets for their crucial roles in cellular processes and involvement in disease initiation and progression. Although some successful chemistry and nanotechnologies have been introduced into peptide PPI modulators to allow cell and tissue permeability, significant challenges remain with regard to the efficient and precise modulation of PPIs within specific cells of diseased tissues, such as solid tumors. Herein, an intratumoral transformable hierarchical framework, termed iPLF, was fabricated via a two-step self-assembly between peptides and lanthanide-doped nanocrystals. In this proof-of-concept study, using NanoEL effect, TME response, and tumor marker targeting, iPLF in vivo delivered the p53-MDM2 modulator DPMI into tumor cells and β-catenin-Bcl9 modulator Bcl9p into tumor stem cells. This crafted programmed nanomedicine with triple-stage delivery and responsiveness accurately modulated the specific intracellular protein-protein interactions, resulting in the suppression of tumor growth and metastasis in vivo, while maintaining a highly favorable safety profile. iPLF reached the goal of accurate, potent, and hazard-free intracellular PPI modulation, thereby providing a means to improve current knowledge of PPI networks and a novel therapeutic strategy for a great variety of diseases.