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.