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

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.

Keywords: PD‐L1 nb; bacterial outer membrane vesicles; immunotherapy; nanozyme; photothermal therapy.