Storming glioblastoma’s fortress: kaempferol-powered spatiotemporal nanotherapy hierarchically breaking-capturing-disarming tumor defenses via programmable metabolic phototherapy amplification

Abstract The efficacy of conventional therapies against glioblastoma (GBM) is limited by a hierarchical defense system comprising the blood-brain barrier (BBB) that restricts the entry of most therapeutic drugs, physical-chemical barriers of tumor that hinder drug penetration and retention, and intrinsic or adaptive metabolic reprogramming that empowers treatment resistance, collectively rendering over 98% of therapeutic agents ineffective. Herein, we propose a ‘breaking-capturing-disarming’ nanotherapeutic strategy via kaempferol-powered spatiotemporal nanotechnology for the sequential dismantling of biological barriers. By loading CaO 2 into hybrid nanoparticles of kaempferol and zinc phthalocyanine 1 (designated KZC NPs), KZC NPs achieve: (1) BBB-breaking via dual-pathway modulation including paracellular-opening and transcellular-enhanced, enabling tumor-tropic drug influx validated by real-time fluorescence/photoacoustic imaging; (2) Tumor-capturing driven by kaempferol-induced protonation gradients and sustained P-glycoprotein (P-gp) inhibition, establishing a positive feedback loop for enhanced and prolonged tumor-specific retention; (3) Tumor microenvironment-disarming mediated via glucose transporters 1 (GLUT-1)-suppression (52.66%) and Ca 2+ -overload (2.42-fold), triggering metabolic crisis while potentiating phototherapy through oxygen-boosted and HSP70-inhibited. The disarming in vivo is verified through 2-Deoxy-2-[¹⁸F]fluoro-D-glucose ( 18 F-FDG) positron emission tomography (PET)-documented reduction in glucose uptake and photoacoustic imaging-confirmed tumor reoxygenation. This kaempferol-induced spatiotemporal programmable strategy induces apoptosis-pyroptosis through physicochemically crosstalk between exogenous photonic intervention and endogenous metabolic disruption. Our work develops programmable barrier-breaching nanoplatforms that overcome conventional drug delivery limitations in glioblastoma, bridging traditional medicine principles with nanotechnology to combat intractable glioblastoma. Graphical abstract