Ultrasound‐Activated Piezoelectric Nanoparticles Targeting and Activating NK Cells for Tumor Immunotherapy

Natural killer (NK) cells can swiftly and efficiently kill tumor cells with low toxicity and show great potential as anticancer agents. However, the hostile tumor microenvironment (TME) reduces the number and functionality of NK cells, leading to tumor progression and the limited therapeutic effect of adoptively transferred NK cells, especially in solid tumors. Here, via mussel-inspired chemistry and targeted antibody modification strategies, functional piezoelectric nanoparticles are designed to target NK cells, named as αCD56-P@BT (for human) or αNK1.1-P@BT (for mouse). With external ultrasonic stimulation, αCD56-P@BT or αNK1.1-P@BT can enhance the cytotoxicity and cytokine-producing ability of NK cells. Mechanistically, the synergistic mechanical and electrical signals generated by ultrasound-irritated P@BT activate the TRP ion channel-mediated calcium ion influx and cytoskeleton rearrangement, in turn improving NK cell migration, infiltration, and function. Upon transfer therapy, NK cells loaded with αNK1.1-P@BT exhibit superior antitumor efficacy in mice with subcutaneous melanoma or intrahepatic cholangiocarcinoma under ultrasonic treatment. Moreover, transfer of αCD56-P@BT loaded NK-92 cells retard the growth of human hepatoma xenograft in immunodeficient mice. This work establishes a wireless electrostimulation strategy integrating ultrasound-responsive nanomaterials to potentiate the cytotoxic activity of NK cells, thereby advancing the clinical translation of NK cell adoptive immunotherapy for solid tumors.