Bimetallic Ions Functionalized Metal–Organic‐Framework Nanozyme for Tumor Microenvironment Regulating and Enhanced Photodynamic Therapy for Hypoxic Tumor

Abstract Photodynamic therapy (PDT), as a light irradiation inducing reactive oxygen species (ROS) generation for cancer treatment, offers facile and promising solutions with respect to spatiotemporal control of ROS generation, and minimizes the systemic toxicity and side effects for highly precise tumor therapy. However, the PDT efficiency is often severely compromised by the complex tumor microenvironment (TME), such as the hypoxic condition and overexpressed antioxidants. Here, for the first time, a bimetallic ion–modified metal−organic framework nanozyme (Zr 4+ ‐MOF‐Ru 3+ /Pt 4+ ‐Ce6@HA, ZMRPC@HA) is designed. ZMRPC@HA with catalase (CAT) and glutathione oxidase (GSHOx) mimetic activities, can efficiently regulate TME by generation of O 2 and deplete the GSH synergistically for enhancing the long‐term PDT efficacy toward the hypoxic tumor. The in vitro cell inhibition and in vivo on tumor xenograft evaluations demonstrate the PDT strategy by using ZMRPC@HA can successfully inhibit the differentiation and proliferation of tumor cells under a 660 nm laser irradiation in deep tissues. These findings open a new avenue for the design of multimetallic ions functionalized MOF‐based nanozymes with multienzyme mimetic activities toward the antitumor and various other biological applications.