Cathepsin B‐Responsive Dendronized‐Hyaluronic Acid Nanomedicine for Simultaneous Cancer Theranostics

ABSTRACT Tumor microenvironment‐responsive imaging‐guided therapy has emerged as a novel approach for malignant tumor prognosis and therapy. A multifunctional nanoscale drug delivery system is often employed to realize diagnosis, treatment, monitoring, and evaluation by combining a therapeutic unit and an imaging unit to enable. In this study, we designed and prepared a theranostic nanomedicine by conjugating a small‐molecular gadolinium chelate (Diethylenetriaminepentaacetic acid Gadolinium[III] chelate, Gd‐DOTA) and a chemotherapeutic drug paclitaxel (PTX) via a cathepsin B‐responsive linker (glycylphenylalanylleucylglycine, Gly‐Phe‐Leu‐Gly, GFLG) onto a peptide dendron‐hyaluronic acid (HA) hybrid. Upon reaching the tumor microenvironment, the GFLG linker was cleaved by overexpressed cathepsin B, leading to simultaneous release of PTX for targeted chemotherapy and Gd‐DOTA for enhanced magnetic resonance imaging (MRI). The experiments demonstrated that the theranostic nanomedicine significantly enhanced MRI contrast and exhibited superior antitumor efficacy in 4T1 breast tumor models without pronounced systemic toxicity. Importantly, under the tumor microenvironment, effective release and clearance of Gd‐DOTA from the hybrid postimaging reduced the risk of long‐term toxicity. This study presents a feasible approach for cancer theranostics by integrating precise imaging, targeted therapy, and rapid clearance of toxic drugs in a single platform. This promising nanomedicine could be explored for clinical translation.