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.