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

Abstract 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.