Size-Controllable DNA Origami-Stacked Gold Nanoparticles for Deep Tumor-Penetrating Therapy

With the rapid development of nanotechnology, researchers have designed a variety of intelligent nanodelivery systems to enhance tumor targeting of anticancer drugs. However, increased tumor accumulation does not indicate deeper penetration in the tumor tissue, without which the tumor cells in the core area cannot be sufficiently killed. Herein, we develop a size-controllable nanoparticle system for deep-penetrating cancer therapy, which will be programmably disassembled with the decrease of the pH from the normal tissue to the tumor microenvironment and to the intracellular area. The integrated nanoparticle is composed of a gold nanoparticle (GNP, ∼30 nm) and a tetrahedral DNA nanostructure (TDN, ∼25 nm) loaded with doxorubicin (DOX). Initially, the nanoparticles maintain a larger size (∼100 nm) to accumulate in the tumor through the enhanced permeability and retention effect. At a pH of about 6.5 at the tumor microenvironment, with the linkage of DNA sequences converting into a triplex structure, the TDNs detach from the GNP and penetrate deeply into the tumor interstitium and then are internalized into the cells. Finally, in acidic lysosomes with pH 5.0, the TDNs release DOX by forming an i-motif structure. This nanosmart delivery system thus shows effective deep penetration into the tumor core with good antitumor efficacy and satisfactory biocompatibility and provides new insights into the development of intelligent nanosystems for anti-cancer treatment.