Activatable Nanovesicle Rewires Immunometabolic Barriers for NIR-II Photoacoustic-Guided Sono-immunotherapy of Glioblastoma

Abstract Glioblastoma (GBM) remains largely refractory to immunotherapy owing to a restrictive brain tumor niche that limits therapeutic access and fosters persistent immune evasion. Here, we present a programmed nanovesicle to sequentially overcome biological barriers and rewire the immune landscape of GBM. The system integrates genetically engineered cytomembrane vesicles displaying a matrix metalloproteinase-responsive Ang2-CD47 nanobody fusion with sono-activatable albumin nanocages coencapsulating a CD73 inhibitor (APCP) and an organic sonosensitizer. Ang2-mediated engagement of low-density lipoprotein receptor-related protein 1 enables blood–brain barrier translocation, whereas proteolytic shedding of the Ang2 corona within the tumor milieu promotes intratumoral retention and unmasks the CD47 nanobody to block the CD47-SIRPα phagocytosis checkpoint. Upon sono-irradiation, the nanovesicle induces sonodynamic cytotoxicity and immunogenic cell death, while triggering self-dissociation for on-demand APCP release. The released APCP further suppresses the CD73-adenosine axis, rescuing effector immune cells from adenosine-mediated dysfunction. These coordinated processes establish a self-reinforcing immune cascade that reprograms GBM into an immunologically permissive niche. Notably, the sonosensitizer possesses NIR-II photoacoustic activity, enabling high-resolution imaging of deep-seated tumors. This nanovesicle elicits durable antitumor efficacy and robust immune remodeling in aggressive and recurrent orthotopic GBM models, offering a promising paradigm for dismantling immunotherapeutic resistance in malignant brain tumors.