###### Abstract  
Microplasma irradiation is a promising technique for the transdermal delivery of high-molecular-weight drugs. In this technique, microplasma components interact with the skin surface or cell membranes, allowing the drugs to penetrate. For efficient and safe drug delivery, it is crucial to understand these interactions. To this end, this study investigated the effects of microplasma irradiation on cellular lipids, particularly those associated with cell membranes. Rat intestinal epithelial cells were treated with microplasma irradiation at two different voltages (4.0 kV or 4.5 kV). An untargeted lipidomic was conducted using liquid chromatography-mass spectrometry (LC/MS) technique. The results revealed that microplasma irradiation at 4.0 kV induces a significant increase in cell membrane lipids within 10 min post-irradiation. All major cell membrane lipids, including phosphatidylcholine, phosphatidylcholine, phosphatidylfenalomarine, phosphatidylserine, and sphingomyelin, exhibited increases of over 25% within this short timeframe. Notably, this effect is transient, as lipid levels return to their baseline after 12 h. Furthermore, no significant differences in live and apoptotic cell percentages were observed between the control and 12 h post-irradiated cells. In contrast, irradiation at 4.5 kV did not elicit significant changes in cell membrane lipids, correlating with the absence of drug absorption under this condition. Hence, our study unveiled a correlation between the rapid increase in cell membrane lipids and enhanced drug absorption in microplasma-irradiated cells. This lipid augmentation potentially enhances membrane fluidity and permeability, thus facilitating drug absorption. Beyond elucidating the mechanisms and safety of microplasma-based drug delivery, our research provides valuable insights for advancing various microplasma-based biomedical technologies. cell membrane; drug delivery; lipid; microplasma +
Footnote †: journal: Medical Imaging and Spectroscopy  
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Footnote 1: email: _Applied_  
**Citation:** [PERSON], [PERSON]. particularly in dermatology, are well-known [4]. Recently, microplasma irradiation has attracted attention for its potential to enhance transdermal drug delivery and cellular drug absorption [5]. In 2017, our group demonstrated the transdermal delivery of a low-molecular-weight drug, cyclosporine A (molecular weight of 1203 Da), using a CAP jet or microplasma irradiation [6]. In conventional drug delivery systems, including oral, parenteral (such as intravenous and intramuscular), inhalation, and transdermal delivery, each approach has its own advantages and limitations. Oral delivery remains the most convenient and widely used method. However, this route faces several challenges, including the first-pass metabolism in the liver, enzymatic degradation, pH variation in the gastrointestinal tract, and potential interactions with food, which can reduce the bioavailability of drugs. Parenteral delivery ensures rapid onset of action and precise dosing, but is often associated with discomfort, pain, and tissue damage at the administration site. Additionally, parenteral administration requires trained healthcare professionals and carries a risk of infection. Inhalation delivery proves effective for treating respiratory conditions, but it faces challenges such as the need for proper coordination during inhalation, device maintenance, and the potential risk of lung irritation or damage. In contrast, transdermal drug delivery offers several advantages, including targeted delivery, painlessness, reduced drug doses and toxicity, avoidance of first-pass metabolism in the liver, and improved drug efficacy and stability. However, certain drugs, especially those with high molecular weights exceeding 500 Dalitons, face limitations in transdermal delivery under normal circumstances. In order to address this challenge, microplasma irradiation emerges as a promising approach to enhance the transdermal delivery of drugs.