Plasma-Nanosecond Pulsed Electric Field Synergy Enhances Multiscale Reactive-Species Transport in Glioma Models.

Abstract

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis and frequent recurrence. Cold atmospheric plasma (CAP) and nanosecond pulsed electric fields (nsPEF) have shown promise for glioma treatment, but their efficacy is limited by insufficient intratumoral delivery of reactive oxygen and nitrogen species (RONS) and spatially heterogeneous treatment responses. Here, we propose an atmospheric pressure plasma jet (APPJ)-nsPEF combination strategy to enhance multiscale RONS transport through electroporation-mediated transport-boundary modulation. Finite element modeling, three-dimensional (3D) hydrogel tumor models, multicellular tumor spheroids, and a subcutaneous glioma model were used to evaluate transport mechanisms and therapeutic efficacy. Modeling showed that nsPEF established a transient membrane-level high-flux transport window, promoting H$_{2}$O$_{2}$ and NO$_{3}^-$ influx and K$^+$ efflux, thereby disrupting redox balance and electrochemical homeostasis. In 3D tumor models, APPJ-nsPEF enhanced intratumoral RONS accumulation, loosened tumor architecture, reduced residual deep-region tumor cells, and suppressed proliferation. In vivo, the combined treatment produced stronger local tumor inhibition than either monotherapy. APPJ-nsPEF enhances antitumor efficacy by coupling plasma-derived RONS generation with electroporation-mediated transport-boundary modulation at cellular and tissue scales. These findings reveal a multiscale synergistic mechanism linking electroporation-regulated RONS transport to biological responses and provide a transport-centered physical combination strategy for glioma treatment.