Virus-inspired nanocages potentiate glioblastoma sonochemotherapy via structure-function mimicry

Sonochemotherapy has emerged as a promising strategy for glioma treatment through synergistic therapeutic effects and reduced systemic toxicity. Nevertheless, clinical translation remains constrained by the hypoxic tumor microenvironment, antioxidant defense mechanism, inadequate tumor accumulation, and suboptimal cellular internalization. Inspired by the rabies virus, we engineered rabies virus glycopeptide-29 (RVG29)-anchored virus-like hollow mesoporous manganese oxide (vHMMn) nanocages co-encapsulating temozolomide (TMZ) and indocyanine green (ICG) (denoted as TI@vHMMnR) for amplified sonochemotherapy through hypoxia relief and glutathione (GSH) depletion. Following tumor accumulation via the enhanced permeability and retention (EPR) effect, TI@vHMMnR nanocages achieved rapid cellular entry through structural-functional mechanisms: Structurally, TI@vHMMnR mimics the rugged and uneven topography of virus's surfaces, thereby enabling spike-facilitated adhesion to tumor cells. Functionally, the interaction of RVG29 with nicotinic acetylcholine receptors (nAChRs) induces receptor-mediated endocytosis, which allows for efficient internalization. Under ultrasound (US) triggering, the nanocages could generate reactive oxygen species (ROS) to induce mitochondrial dysfunction. Meanwhile, the nanocages could catalytically convert endogenous hydrogen peroxide (H₂O₂) into oxygen to relieve tumor hypoxia to improve sonodynamic efficacy. Moreover, the nanocages could be efficiently biodegraded by intracellular overexpressed GSH inside tumor cells to result in the burst release of TMZ, thus inducing effective DNA double-strand breakage. More importantly, this depletion of GSH could weaken tumor cells' antioxidant defense mechanism to amplify the sonochemotherapy. Our rabies virus-inspired nanocages with structure-function mimicry could significantly improve the therapeutic efficiency through sonochemotherapy coupled with hypoxia relief and GSH exhaustion, offering a new avenue for Glioblastoma (GBM) therapy. STATEMENT OF SIGNIFICANCE: Glioblastoma (GBM) remains a lethal brain cancer with limited treatment efficacy due to hypoxic microenvironments, glutathione (GSH)-mediated antioxidant defenses, and poor blood-brain barrier (BBB) penetration. This work overcomes these barriers by engineering rabies virus-inspired manganese oxide nanocages (TI@vHMMnR) that co-deliver temozolomide and indocyanine green. The nanocages mimic viral surface topography and receptor-targeting mechanisms (RVG29-nAChR) to enhance tumor accumulation and cellular uptake. Crucially, they simultaneously relieve hypoxia via catalytic H₂O₂ decomposition and exhaust GSH to amplify ultrasound-triggered reactive oxygen species (ROS) generation. This dual microenvironment remodeling synergizes sonodynamic therapy with chemotherapy, achieving 95.2 % tumor growth inhibition in orthotopic GBM models. The biomimetic nanoplatform offers a transformative strategy for precision glioblastoma therapy by integrating structural mimicry, self-amplifying ROS cascades, and spatiotemporally controlled drug release.