Glycyrrhizic acid-based nanotheranostic system to enhance photothermal immunotherapy by suppressing HSP90 and remodeling tumor microenvironment

Anticancer photothermal therapy efficacy is currently restricted by heat shock protein (HSP90)-mediated thermoresistance, immunosuppressive microenvironment, and poor delivery efficiency of photosensitizers. At present, the "all-in-one" therapeutic system that can simultaneously achieve tumor-targeted delivery, efficient photothermal therapy, and tumor immune enhancement effects is desperately needed. We previously fabricated Glycyrrhizic acid (GL)-based lipid nanoparticles (GLPs) that possess hepatocellular carcinoma (HCC) targeting and improved membrane stability. Interestingly, GL exhibits the potential to inhibit the up-regulated HSP90 and regulate the immunosuppressive tumor microenvironment. Herein, the near-infrared photosensitizer IR780 was efficiently encapsulated into GLPs to promote photothermal enhancement and synergistic immunosuppressive anti-tumor effects. Under the irradiation of NIR light, the IR780 GLPs effectively enhance the PTT efficacy on the HCC-bearing mice model via suppressing HSP90 expression with the combination of GL. Furthermore, IR780 GLPs exhibited strong HCC targeting ability, effectively downregulating the expression of immunosuppressive Treg cells, promoting the repolarization of M2 macrophages to M1 macrophages, increasing the infiltration of cytotoxic CD8⁺T cells and downregulating the expression of TGF-β and IL-10, upregulating IL-12, TNF-α, and IFN-γ, reshaping the tumor immunosuppressive microenvironment. Overall, we developed a novel GL-based lipid nanoparticle system encapsulating IR780 to amplify the synergistic effects of chemo-PTT for HCC treatment.