Selective and spatiotemporal‑resolved nano-PROTAC for lung cancer therapy.

The Proteolysis-Targeting Chimeras (PROTAC) technology has become a promising tool in lung cancer therapy. The PROTAC regents targeting to Bromodomain-containing Protein 4 (BRD4) showed effective induction of apoptosis in lung cancer cells. However, the application of this kind of PROTAC regents is still hindered by the low tissue specificity, solubility, and detectability. Herein, we developed a selective and spatiotemporal‑resolved nano-PROTAC, which was constructed using the functional polymer Poly(lactic-co-glycolic acid)-Polyethylene glycol 2000-Maleimide (PLGA-PEG-Mal) to load PROTAC regent dBET6 and the fluorescence dye, and further modification with aptamer targeting to the lung cancer cells. The drug-loaded nanoparticles can be uptaken by lung cancer cells effectively, inducing the complete degradation of BRD4 and effective apoptosis of lung cancer cells. In vivo experiments indicated that the aptamer-modified nanoparticles accumulated in the tumors, which led to the effective suppression of tumor growth in the tumor-bearing mouse model. Furthermore, this type of nano-PROTAC was endowed with real-time tracking capability, avoiding the extra and tedious modifications. The integrated diagnosis and treatment system showed great promise in lung cancer therapy.