Cyclodextrin-Functionalized Gold Nanorods Loaded with Meclofenamic Acid for Improving N6-Methyladenosine-Mediated Second Near-Infrared Photothermal Immunotherapy

Cancer immunotherapy has achieved considerable clinical progress in recent years on account of its potential to treat metastatic tumors and inhibit recurrence. However, low patient response rates and dose-limiting toxicity are the major limitations of immunotherapy. Nanoparticle-based photothermal immunotherapy can amplify antitumor immune responses, although poor tumor penetration depth of near-infrared radiation (NIR) and the immunosuppressive tumor microenvironment significantly dampen its effects. We designed a nanoplatform based on gold nanorods for NIR-II-mediated photothermal therapy (PTT) combined with N6-methyladenosine (m6A) demethylase inhibition to achieve enhanced photothermal immunotherapy against prostate cancer. The GNRs were assembled layer by layer with polystyrenesulfonate as the interconnecting layer and then coated with a cationic polymer of γ-cyclodextrin (CD)-cross-linked low-molecular-weight polyethylenimine that was conjugated to an 8-mer peptide targeting the prostate tumor-specific gastrin-releasing peptide receptor. The m6A RNA demethylase inhibitor meclofenamic acid (MA) was then loaded into the CD cavity through hydrophobic interactions. GNR-CDP8MA specifically targeted the prostate tumor cells and selectively accumulated at the tumor site in vivo. In addition, GNR-CDP8MA almost completely ablated prostate cancer cell-derived tumors upon 1208 nm laser irradiation. Mechanistically, NIR-II triggered the release of MA from GNR-CDP8MA, which increased global mRNA m6A methylation and decreased the stability of PDL1 transcripts. Furthermore, GNR-CDP8MA-mediated PTT-induced immunogenic cell death in the primary tumor and consequently enhanced antitumor immunity by activating the antigen-presenting dendritic cells and tumor-specific effector T cells in the metastatic tumors. This study offers insights into synergistic m6A RNA methylation and PTT as an effective strategy for cancer immunotherapy.