Stimuli-Responsive DNA Tetrahedral Lysosome-Targeting Chimeras for Enhanced HER2 Protein Degradation.

Overexpression and abnormal activation of membrane proteins promote malignant tumor cell proliferation, while traditional interventions are often limited by drug resistance caused by target mutations. Here, we designed a stimulus-responsive DNA tetrahedron lysosome-targeted chimera (tFNA-LYTAC) strategy for degrading embrane proteins. Two tetrahedra are modified with trivalent HER2 aptamers (tFNA1-Apt) and trivalent IGF2R aptamers (tFNA2-Apt), enabling targeted binding to HER2 and IGF2R, and are then self-assembled into tFNA-LYTAC under VEGF stimulation to promote HER2 degradation. The trivalent aptamer modification strategy significantly enhances the overall binding capacity of tFNA1-Apt to cells. Importantly, tFNA-LYTAC formed only in the presence of VEGF, integrating tetrahedral multivalent aptamer targeting with stimulus responsiveness to improve the degradation specificity. VEGF-responsive tFNA-LYTAC promoted HER2 degradation and suppressed the phosphorylation of key downstream signaling proteins. The study innovatively proposes a "target recognition-stimulus response-endocytic degradation" mode that selectively regulates membrane proteins through programmable multivalent aptamer nanostructures.