Nanomotors activating both cGAS-STING pathway and immune checkpoint blockade for tumor therapy and bioimaging

Abstract

Cellular innate immune response is closely related to cGAS-STING pathway and PD-1/PD-L1 immune checkpoint blockade. The lack of tissue penetration of STING agonists and nanomedicines in conventional approaches reduces their immunotherapeutic efficacy. At the same time, because the cGAS-STING signaling pathway is silent in many breast cancer cells, it cannot play its role. To address these challenges, here, we developed a silica nanomotor based on bubble propulsion. Its hollow structure was packed with the photosensitizer Ce6 molecule. Under 808 nm laser irradiation, Ce6 produced 1O2, which lead to intracellular DNA damage and further activated the cGAS-STING pathway, stimulating the maturation of DC cells, and enhancing the tumor infiltration of CD8+ T cells. The nanomotor had an asymmetrical structure. One side of the nanomotor was modified with Pt nanoparticle. This asymmetric modification can catalyze H2O2 in the environment, producing an asymmetric concentration of O2, which realized the bubble driving nanomotor movement and enhances penetration into breast cancer cells of nanomotor. The other side of the nanomotor was modified the LXL-1 aptamer, triphenylphosphine and peptide CLP002. Peptide CLP002 specifically bound residues of PD-L1 interaction with PD-1, blocked the mutual binding between PD-1 and PD-L1, and further improved the immune response ability of tumor infiltrating T cells. In this study, we developed a multi-pronged immunotherapy strategy of intelligent target finding, breaking through the physiological barrier through kinetic energy, accurately intervening the target and bioimaging, providing a new idea for breast cancer cells targeted therapy.