Multimodal In-vitro tumour starvation therapy using enzyme-driven piezoelectric nanosystems utilizing ultrasound effect.

Several types of tumours and their complexity have been a challenge for experts in medical research, driving the need for innovative approaches. Recent exploration in various nano systems aims to address this issue by targeting tumours more precisely, thereby improving treatment efficacy with minimum adverse reactions. In this study, we introduce a glucose-responsive (enzyme powered), piezoelectric nanohybrid platform composed of a core-shell architecture, where Barium Titanate nanoparticles (BTNPs) forms the ultrasound-responsive piezoelectric core, and the mesoporous silica nanoparticles (MSNPs) as the functionalised shell. The shell is engineered with Glucose Oxidase (GOx) enzyme on its surface and loaded with Ethylenediaminetetraacetic acid (EDTA) in the porous structure. These nanosystem (GOx-MSBTNPsEDTA) are designed to target tumour cells in 3D spheroids, with controlled release of EDTA at the target site upon ultrasound (US) application. The GOx-MSBTNPsEDTA functionalization induces localized catalytic glucose consumption, generating asymmetric chemical gradients that enhance nanosystem diffusion within tumour-like environments, which utilizes glucose that is naturally abundant in the tumour microenvironment. This model demonstrated glucose-dependent enhancement in nanosystem mobility and spatial redistribution within 3D tumour spheroids, along with the controlled release of EDTA upon US application. This combination of enzyme-driven motion and US-stimulated drug release displays substrate-dependent enhanced diffusion along with the precise EDTA release, and deeper penetration into the tumour tissue. This study establishes an enzyme-activated, ultrasound-responsive nanohybrid platform that integrates metabolic modulation and externally triggered cargo release for tumour starvation therapy.