Nanodrug with dual-sensitivity to tumor microenvironment for immuno-sonodynamic anti-cancer therapy.

Although a combination with photodynamic therapy (PDT) is a potential means to improve the immune checkpoint blockade (ICB)-based anticancer immunotherapy, this strategy is subjected to the extremely poor light penetration in melanoma. Herein, we develop a lipid (LP)-based micellar nanocarrier encapsulating sonosensitizer chlorin e6 (Ce6) in the core, conjugating anti-PD-L1 antibody (aPD-L1) to the interlayer through MMP-2-cleavable peptide, and bearing a PEG coating sheddable at low pH value (≈6.5) of tumor microenvironment. The unique nanocarrier design allows a tumor-targeting delivery to activate the anti-tumor immunity and meanwhile to reduce immune-related adverse effects (irAEs). Moreover, a sonodynamic therapy (SDT) is triggerable by using ultrasonic insonation to produce tumor-killing reactive oxygen species (ROS), thereby bypassing the poor light penetration which restricts PDT in melanoma. A combination of SDT with aPD-L1 immunotherapy effectively promotes tumor infiltration and activation of cytotoxic T cells, which resulted in robust anti-cancer immunity and long-term immune memory to effectively suppress melanoma growth and postoperative recurrence. This strategy for tumor-targeting codelivery of immune checkpoint inhibitors and SDT agents could be readily extended to other tumor types for better immunotherapeutic outcome and reduced irAEs.