Synergistic Transdermal Drug Delivery via Piezoelectric P(VDF-TrFE)/Chitosan/Gold Nanohybrid Electrospun Membranes Combined with Targeted Ultrasonic Sonoporation

<jats:p>Transdermal administration of therapeutic ointments for cutaneous malignancies and severe localized bacterial infections is fundamentally constrained by the stratum corneum (SC) barrier. Here, we report a multi-modal transdermal drug delivery system comprising an electrospun piezoelectric Poly(vinylidene fluoride-trifluoroethylene)/Chitosan/Gold nanoparticle (P(VDF-TrFE)/CS/AuNP) membrane coupled with a custom-designed, multifrequency ultrasonic excitation platform (1.0–3.0 MHz). The synthesized nanohybrid membrane exhibited superior biocompatibility, enhanced mechanical flexibility, and intrinsic acoustic impedance matching with human skin. FTIR and XRD analyses confirmed high 𝛽-phase crystallinity (82.4 ± 1.8%) in the electrospun fibers, crucial for efficient electromechanical transduction. A custom dual-layer Printed Circuit Board (PCB) integrating an ATmega328P microcontroller and an AD9833 Direct Digital Synthesis (DDS) IC was fabricated to drive a PZT-5H ceramic transducer via an LC Butterworth impedance matching network. In vitro permeation tests using Franz diffusion cells demonstrated a 5.20 ± 0.28-fold increase (𝑝 &lt; 0.001, 𝑛 = 6) in the flux of a model oncology drug (5-Fluorouracil) across porcine skin under 2.4 MHz ultrasonic stimulation (1.2 W/cm2) compared to passive diffusion. Cytotoxicity assays (MTT) using L929 fibroblasts confirmed zero allergic response and 96.8 ± 1.4% cell viability for the composite substrate. This integrative platform provides a non-invasive, highly controllable strategy for rapid local drug bio-absorption without systemic toxicity.</jats:p>