Synergizing sono-piezo with exosome suppression using doping-engineered hydroxyapatite for potentiated tumor treatment through immunoactivation

Piezoelectric nanomaterials that generate reactive oxygen species (ROS) through piezoelectric polarization under mechanical stimulation have emerged as a promising cancer therapy platform. However, their potential is limited by poor piezoresponse, low catalytic efficiency, and the exacerbation of immunosuppression due to ROS-induced release of tumor-derived exosomes. In this study, we employed a doping-engineered strategy by incorporating manganese ions (Mn(2)⁺) into hydroxyapatite (HAP) to enhance its piezocatalytic performance, while combining exosome inhibition to achieve a synergistic improvement in tumor therapy. Mn(2)⁺-doped HAP was synthesized via a one-pot hydrothermal method and subsequently modified with a ROS-cleavable lipid, DSPE-TK-mPEG. During the modification process, the exosome inhibitor GW4869 was loaded, resulting in the formation of GW4869-loaded Mn(2)⁺-HAP-Lipid nanocomposites (abbreviated as GMHL). The introduction of Mn(2+) significantly reduced the bandgap of HAP, thereby enhancing its piezoelectric catalytic activity to generate ROS under ultrasound (US) stimulation, which triggered the cleavage of ketone-thiol bond in DSPE-TK-mPEG and led to the efficient release of GW4869. In multiple tumor models, GMHL effectively retard tumor growth and inhibited the production of tumor-derived exosomal PD-L1 upon US stimulation, thereby triggering an anticancer immune response through modulation of the immunosuppressive tumor microenvironment.