Nanozyme‐Based Biomimetic Intelligent Immune Organelles for the Treatment of Bladder‐Metastasized Tumors

Abstract

Abstract Immune‐checkpoint inhibitors (ICIs) have transformed the treatment of bladder cancer. However, inadequate immune responses restrict their clinical application. To increase the efficacy of ICIs, a nanozyme‐based intelligent biomimetic immune organelle has been developed for the treatment of metastatic bladder tumors. Initially, a reactive oxygen species (ROS)‐responsive nanozyme platform is constructed using 1,2‐Distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐Tk‐(polyethylene glycol) (DSPE‐TK‐PEG) to assemble ultrasmall p‐d orbital hybrid bimetallic rhenium (Re)‐palladium (Pd) nanozyme. The orbital hybridization between the Re and Pd atoms significantly enhances the peroxidase (POD)‐like activity of the Pd nanozyme. Additionally, the RePd nanozyme exhibits notable glutathione oxidase (GSH‐OXD)‐like activity, which reduces the clearance of ROS and enhances its capacity to induce oxidative stress. This platform is then coated with bacterial outer membrane vesicles (OMVs) engineered with PD‐L1 nanobody (nb), which form RePd@OMVs PD‐L1 nb . Upon entry into the tumor microenvironment, the RePd nanozyme is released, and the PD‐L1 nb specifically binds to the tumor cell membrane to relieve its inhibition of T cells. Moreover, RePd@OMVs PD‐L1 nb demonstrates enhanced tumor accumulation and promotes synergistic catalytic‒photothermal therapy, inducing immunogenic cell death and promoting immune activation through the release of adjuvants. Consequently, the efficacy of PD‐L1 nb is significantly improved, leading to the effective eradication of tumor cells and the inhibition of recurrence and metastasis.