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This research aims to develop a novel nanotherapeutic strategy utilizing kaempferol to dismantle barriers hindering glioblastoma treatment.

May 14, 2026Advanced Composites and Hybrid Materials0 citationsOpen Access

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

KSKunhui SunTianjin University of Traditional Chinese Medicine SLSitong LaiTianjin University of Traditional Chinese Medicine MLMengnan LiShenzhen Institute for Drug Control

Key Points

This research aims to develop a novel nanotherapeutic strategy utilizing kaempferol to dismantle barriers hindering glioblastoma treatment.
Developed a kaempferol-powered nanoplatform with CaO2 and zinc phthalocyanine.
Utilized real-time fluorescence/photoacoustic imaging to assess BBB penetration and drug retention.
Examined tumor reoxygenation and glucose uptake reduction through PET imaging.
Achieved 52.66% GLUT-1 suppression and significant tumor microenvironment disarming.
Documented 2.42-fold Ca2+ overload leading to metabolic crisis.
Induced apoptosis-pyroptosis through engineered metabolic disruption and photonic interventions.

Abstract

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-2-¹⁸Ffluoro-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

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