Permeabilization of biomembranes by polycationic peptides is known to depend on the membrane potential, although the exact mechanism of this process is not yet completely defined, to be effectively controlled. We quantified peptide-assisted permeabilization of red blood cells (RBCs) using a custom system that delivered microsecond bipulses configured as bimonopolar (BMP; same polarity) or bipolar (BP; opposite polarity), varying the inter-monopulse interval ( \(\:{t}_{2}\) ). In RBC suspensions, bulk light transmittance at 650 nm showed that BMP yielded higher permeabilization effect than BP at short \(\:{t}_{2}\) , whereas lengthening \(\:{t}_{2}\) mitigated bipolar cancellation and increased BP responses. Membrane surface charge modulation by moderate concentrations of deoxycholate and spermine increased and decreased, respectively, membrane permeabilization effects of polycationic peptides. Complementary measurements in planar lipid bilayers (BLMs) under an applied command voltage ( \(\:{V}_{\text{a}\text{p}\text{p}}\) ) with polarity alternation showed remarkable conduction at negative bias, essentially decreased in the presence of 1 mM Mg2+. Infrared thermometry over RBC suspension revealed modest heating (≈ 2.5–6 °C), equal for BMP and BP applications, indicating an electrical rather than thermal origin for waveform effects. Finally, the designed electroporation protocols allow controlled short-time permeabilization of cell membrane that might be useful for biotechnological applications and therapeutic delivery.
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