Abstract
A major limitation of tumor antiangiogenic therapy is the pronounced off-target effect, which can lead to unavoidable injury in multiple organs. Ensuring sufficient delivery and controlled release of these antiangiogenic agents at tumor sites is crucial for realizing their clinical application. Here, we develop a smart DNA-based nanodrug, termed Endo-rDFN, by precisely assembling the antiangiogenic agent, endostar (Endo), into a reconfigurable DNA framework nanotube (rDFN) that could recognize tumor-overexpressed nucleolin to achieve the targeted delivery and controllable release of Endo. Endo-rDFN can not only effectively enhance the tumor-targeting capability of Endo and maintain its efficient accumulation in tumor tissues but also achieve on-demand release of Endo at tumor sites via the specific DNA aptamer for tumor-overexpressed nucleolin, named AS1411. We also found that Endo-rDFN exhibited significant inhibition of angiogenesis and tumor growth, while also providing effective protection against multiorgan injury (heart, liver, spleen, kidney, lung, etc.) to some extent, without compromising the function of these organs. Our study demonstrates that rDFN represents a promising vector for reducing antiangiogenic therapy-induced multiorgan injury, highlighting its potential for promoting the clinical application of antiangiogenic agents.