Ion-Engineered Clay Nanozyme via Tumor Microenvironment Remodeling for Enhanced Tumor Therapy

Metal ions show tremendous promise for tumor therapy due to their critical roles in many important catalytic circulations and immune processes. However, the valence state variability and systemic side-effects of metal ions cause ineffective ion enrichment in tumor cells, which limit their further application. Here, a Mn³⁺ ion delivery system (Mn-HNT) is constructed based on halloysite nanotubes (HNT) via an ion-engineered strategy. Due to the stabilizing effect of HNT on Mn³⁺ ions, Mn-HNT not only maintained the valence state of Mn³⁺ ions, but also presented strong catalase (CAT)- and glutathione oxidase (GSHOx)-like catalytic activity to catalyze O₂ generation and GSH consumption to relieve the inhibition of tumor microenvironment on photodynamic therapy (PDT). After further coordination with the photosensitizer porphyrin (TCPP), obtained TCPP-Mn-HNT not only inherited the catalytic properties of Mn-HNT to produce oxygen and consume GSH, but acted as photosensitizer for ROS accumulation to effectively destroy tumor cells. Moreover, TCPP-Mn-HNT can promote the maturation of dendritic cells (≈2.8 times), and present the tumor antigen triggered by PDT to T cells to strengthen high-efficient tumor therapy. The study provides new opportunities for designing metal ion delivery system with versatile biofunctions and offers a paradigm of synergistic metal-ion-mediated tumor therapy.