NIR-II Photoacoustic Imaging-Guided Chemo-Photothermal Therapy Using PA1094T Combined with Anti-CD47 Antibody: Activating Pyroptosis against Orthotopic Glioblastoma.

Treating glioblastoma (GBM) with single-agent chemotherapy is often ineffective due to inefficient drug delivery and the immunosuppressive tumor microenvironment, which leads to drug resistance. Strategies that activate programmed cell death mechanisms and repolarized tumor-associated macrophages toward an antitumoral M1-like phenotype can help reverse the immunosuppressive tumor microenvironment. In this study, a novel approach using NIR-II (1000-1700 nm) photoacoustic imaging (PAI)-guided chemo-photothermal therapy is presented. NIR-II imaging, with its superior tissue penetration and reduced background noise, enables precise tumor targeting. A targeted nano prodrug is developed using poly (lactic-co-glycolic acid) nanoparticles loaded with A1094 dye and temozolomide (TMZ), coupled with an anti-CD47 antibody. This system employs synergistic chemo-photothermal therapy activated by NIR-II light, inducing apoptosis, pyroptosis, and T-cell activation. PAI provides rapid, point-of-care GBM diagnosis, and highlighted the effective targeting of the PA1094T nanoplatform. In a recurrent GBM model, the combination of PA1094T and anti-CD47 antibody significantly enhances cancer cell phagocytosis and effectively remodels the immunosuppressive microenvironment, resulting in better therapeutic outcomes compared to conventional therapies. These results indicate that this NIR-II PAI-guided drug cocktail therapy is a promising strategy for treating GBM, potentially addressing drug resistance and improving treatment efficacy through enhanced targeting and immunomodulation.