Depolymerizable Enzymatic Cascade Nanoreactor for Self‐Enhancing Targeting Synergistic Tumor Therapy

Abstract Traditional targeting strategies require nanoparticles (NPs) to penetrate the vascular wall to bind tumor cell surface receptors, resulting in a small proportion of drugs that achieve targeting delivery. Based on this, a novel design of self‐enhancing targeting to tumor vascular sites has been proposed and needs to meet two preconditions: 1) It can efficiently bind to P‐selectin overexpressed by activated tumor vascular endothelial cells. 2) It can release reactive oxygen species (ROS) to the tumor site and activate resting vascular endothelial cells, thus providing more targets for subsequent preparations. Besides, to overcome the limited penetration of the tumor site, a variable‐size system needs to be designed. Red light carbon dots nanozyme (Fe(III)‐CDs) and glucose oxidase (GOx) are combined to form the enzymatic cascade nanoreactor FG. As a natural ligand of P‐selectin, fucoidan (Fu) is coated on the surface of L‐arginine‐composite FG to obtain FGA@Fu. It is demonstrated that FGA@Fu can realize weak acid/photothermal responsive depolymerization to enhance the penetration to tumors with controlled ROS release. Inspiringly, FGA@Fu can achieve “targeting‐activation‐(self‐enhanced targeting)” to tumor vasculature with good fluorescence tracking. In vivo anti‐tumor experiments showed that FGA@Fu has excellent cascade enzyme catalysis/gas/photothermal combination therapy effect and strong inhibition of tumor metastasis.