Multifunctional nanozymes for sonodynamic-enhanced immune checkpoint blockade therapy by inactivating PI3K/AKT signal pathway.

Abstract

Insufficient activation efficacy and tumor immunosuppressive microenvironments hinder the infiltration of cytotoxic T lymphocytes (CTLs) for effective immunotherapy. Herein, the pH-selective multienzyme-mimetic nanozymes have been developed based on Pd-hemoporfin (Pd⁰/Pd²⁺‒H) nanoagents for tumor sono-immunotherapy via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway inactivation. The Pd⁰/Pd²⁺‒H is capable of catalase-mimetic, peroxidase-mimetic, and sonodynamic effects, creating an O₂-rich environment and elevating the reactive oxygen species (ROS) levels. The elevated ROS levels down-regulate the expression of PI3K and p-AKT on both gene and protein levels, leading to PI3K/AKT pathway inactivation. Subsequently, the augmented immunogenic cell death effectively recruits dendritic cells, presents tumor-associated antigens, and activates antitumor T-cell immunity. As a result, the combination of Pd⁰/Pd²⁺‒H and anti-programmed cell death protein ligand 1 results in growth restraints of primary and precaution of tumor metastases. This work offers insights into developing multienzyme-mimetic nanozymes in signaling pathway regulation and antitumor strategy.