The Carbonic Anhydrase IX-Activated Nanosensor for Dual-Modal Imaging and Synergistic Phototherapy of Glioblastoma.

Precise diagnosis and treatment of glioblastoma (GBM) remain challenging. The overexpression level of carbonic anhydrase IX (CA IX), a key biomarker for GBM, is correlated with tumor malignancy. Herein, we reported a CA IX-activated nanosensor (MPC@BDPCA NPs) for near-infrared imaging and synergistic phototherapy of orthotopic GBM. The tailor-made core agent, a BODIPY derivative (BDPCA) incorporates a benzenesulfonamide moiety that selectively binds to CA IX, inducing rotational restriction of the probe and resulting in fluorescence turn-on response. Owing to this specific activating mechanism, BDPCA enables a high-contrast fluorescence and photoacoustic dual-modal imaging for quantitative CA IX sensing. Notably, an extended π-conjugation combined with a donor-acceptor molecular design optimizes both radiative and nonradiative decay pathways, affording efficient photothermal conversion and reactive oxygen species generation under 660 nm irradiation. To enhance blood-brain barrier (BBB) penetration in orthotopic GBM models, BDPCA was encapsulated within pH-degradable polymer shell via in situ polymerization, employing 2-methacryloyloxyethyl phosphorylcholine (MPC) as monomer to improve biocompatibility and facilitate receptor-mediated BBB transport. The resulting MPC@BDPCA NPs exhibit selective CA IX sensing, multimodal imaging capability, efficient BBB penetration, and potent synergistic phototherapy. This work highlights a versatile nanoscale sensing and diagnostic platform for precision imaging and therapeutic intervention of GBM.