Robust and Tumor-Environment-Activated DNA Cross-Linker Driving Nanoparticle Accumulation for Enhanced Therapeutics

Agglomeration of therapeutic nanoparticles in response to tumor microenvironments is a promising approach to enhance drug accumulation and improve therapeutic efficacy. Cytosine-rich DNA sequences show potential as ideal cross-linkers to drive nanoparticle agglomeration because they can sensitively respond to weak acidity and form interchain folding. However, the in vivo application of DNA is generally limited by its poor biostability; as a consequence, modifications with unprotected DNA cross-linkers can enhance the accumulation of nanoparticles twofold at the tumor site. Facing this challenge, we have designed and developed a protection and tumor-environment activation strategy to enable the in vivo application of a DNA cross-linker. Specifically, reactive oxygen species (ROS)-responsive polyethylene glycol (PEG) was modified on the nanoparticle surface together with the DNA crosslinker, which protects DNA from degradation during the blood circulation; meanwhile, when arriving at the tumor site, the nanoparticles shed the PEG shell as a response to ROS to uncover and activate the DNA cross-linkers. Using this strategy, a sevenfold enhancement in tumor accumulation was achieved owing to both superior pH sensitivity and improved stability of DNA cross-linkers. Finally, significantly improved therapeutic efficacy in in vivo anticancer treatment was realized by using this agglomeration strategy driven by protected and stimuli-activated DNA cross-linkers.