Cascade piezocatalytic nanoprodrug for synergistic piezocatalytic therapy and sono-activated chemotherapy-augmented immunotherapy

Abstract

Immune checkpoint blockade (ICB) has shown great promise in the management of various cancers. However, only a small percentage of patients profit from ICB therapy. Immunogenic cell death (ICD) has demonstrated its specific capability in reconstructing the tumor microenvironment (TME) and activating anti-tumor immunity. Herein, an ICD cascade enhancement based on BPTL nanoreactors is proposed to overcome the inadequate damage-associated molecular patterns of ICD inducers. BPTL nanoreactor is formed by incorporating the piezocatalytic BaTiO₃ (T-BTO) nanoparticles and paclitaxel (PTX) prodrug that responds to reactive oxygen species (ROS) into liposome nanoparticles for synergistic piezocatalytic and sono-activated chemotherapy (SACT)-augmented immunotherapy. Ultrasound (US) irradiation of the designed BPTL initiates a superior piezodynamic effect and produces ROS by piezocatalytic therapy to trigger ICD. Subsequently, the generated ROS breaks up the thioketal bonds in BPTL, thereby leading to the on-demand release of PTX for SACT and augmented ICD activation. In vivo evaluation demonstrated that BTPL with US irradiation significantly eradicated primary and distant metastatic tumors and markedly prevented the lung metastasis. This nanoplatform combines US-triggered piezocatalytic therapy and SACT for ICD stimulation, providing a robust strategy for amplifying piezocatalytic effect-mediated immune response against tumors.