pH/ATP cascade-responsive nano-courier with efficient tumor targeting and siRNA unloading for photothermal-immunotherapy

Abstract Tumor delivery of programmed death-ligand 1 (PD-L1) siRNA is promising to enhance photothermal therapy (PTT) caused anti-tumor immunity. However, the poor tumor targeting efficiency and insufficient gene release in tumor cells restrict curative effect. Herein, phenylboronic acid (PBA)-based tumor targeting and rapid gene release nano-courier is constructed by encapsulating PD-L1 siRNA (siP) and IR780 (a photothermal agent) in pH/ATP cascade-responsive micelle. The nano-courier can be detached long-circulating PEG shell in a weakly acidic tumor microenvironment, resulting in increased positive charge and PBA exposure for facilitating the penetration and uptake of nano-courier against tumors with overexpressed sialic acid (SA) residues. Subsequently, the intracellular ATP binding with PBA reducing the positive charge of nano-courier could effectively trigger rapid uploading of siP into cytosol. Both in vitro and in vivo studies proved the nano-courier has good performance on PD-L1 silencing on tumor cells. PTT with systemic antitumor immune responses triggered by efficient PD-L1 silencing completely ablated 4T1 orthotopic tumor, suppressed distant tumors growth and metastasis as well as reduced the tumor recurrence.