Synergistic mechanism of plasma and melittin-induced membrane perforation in sialic acid-targeted cancer cells

The combined application of cold atmospheric plasma (CAP) and melittin (MEL) has emerged as a promising anticancer strategy. However, the molecular basis underlying their synergy remains unclear. Sialic acid, which is typically overexpressed on cancer cell membranes, modulates surface charge and oxidative sensitivity. Sialic acid also provides binding sites for cationic peptides, positioning it as a key mediator of CAP-MEL synergy. Here, we established a plasma-sialic acid-MEL simulation model to investigate how CAP-induced electric fields, the MEL concentration, and plasma-generated reactive oxygen and nitrogen species (RONS) collectively shape membrane permeability, energy barriers, and pore dynamics. The simulations revealed that sialic acid modification increases the electrostatic affinity of MEL for the membrane, thereby promoting its translocation and disruption under the influence of a nanosecond pulsed field (0.326 V/nm). Concurrently, RONS-induced lipid oxidation reduced membrane stability and amplified electro-molecular coupling. The extent of this synergy depends on the peptide-to-lipid ratio (P/L). For P/L = 4/128, sialic acid-enriched membranes exhibited notable permeability and RONS influx levels, whereas healthy-cell models experienced only fleeting perturbations. Overall, our findings reveal a threefold synergistic mechanism at the membrane level: sialic acid mediates selective targeting, the electric field regulates transmembrane energy barriers and drives field-dependent transport, and the melittin dosage dictates membrane permeability and the magnitude of structural disruption. In addition, RONS-induced lipid oxidation further amplifies this selective membrane-damaging effect. This multiscale coupling provides fresh molecular insight for designing plasma-assisted, peptide-based anticancer therapies that combine high precision with minimal collateral damage.