Gossypol‐Crosslinked Nanoclusters of Ultrasmall Iron Oxide Nanoparticles for Ultrasound‐Enhanced Precision Tumor Theranostics

Development of tumor microenvironment (TME)‐responsive nanomedicines with simple components for precision tumor theranostics still maintains a great challenge. Here, the design of an intelligent nanocluster (NC) system assembled from gossypol‐mediated crosslinking of phenylboronic acid‐modified ultrasmall iron oxide nanoparticles (USIO NPs) is presented. The gossypol functions as both a chemotherapy (CT) drug and a crosslinker through phenylborate ester bonds that are sensitive to both reactive oxygen species (ROS) and pH. The developed gossypol‐USIO NCs (for short, G‐USIO NCs), having a size of 34.2 nm, possess stability under physiological conditions, enable intracellular ROS generation and glutathione depletion to modulate TME, promote apoptosis of cancer cells in vitro, and inhibit tumor/lung metastasis in vivo through gossypol‐mediated CT and USIO‐mediated chemodynamic therapy owing to the ROS‐ and pH‐triggered dissociation of the NCs to release gossypol and Fe at the tumor site. Likewise, the dissociated USIO NPs from the NCs afford TME‐facilitated T1‐weighted magnetic resonance (MR) imaging. Furthermore, the effects of the tumor T1 MR imaging and the combination therapy can be elevated by ultrasound‐targeted microbubble destruction‐induced cavitation and sonoporation. The designed G‐USIO NCs with simple ingredients are likely developed to be a promising theranostic nanomedicine formulation for ultrasound‐facilitated precision theranostics of various tumor types. Intelligent nanoclusters (NCs) of ultrasmall iron oxide nanoparticles (USIO NPs) are formed through gossypol‐mediated crosslinking of phenylboronic acid‐modified USIO NPs. The developed USIO NCs display tumor microenvironment‐responsive release of both gossypol and Fe, generate intracellular reactive oxygen species, and deplete cellular glutathione, thus allowing for ultrasound‐enhanced magnetic resonance imaging and combined chemo‐chemodynamic therapy of tumors.