Lipid analysis in biological structures – Is time-of-flight secondary ion mass spectrometry a valuable tool in nano-lipidomics?

<ns3:p>&lt;br&gt;&lt;b&gt;Introduction:&lt;/b&gt; Lipids are crucial biomolecules that confer structural integrity to cell membranes, facilitate signalling and regulate energy dynamics. Dysregulation of lipids is associated with various diseases, including diabetes, chronic inflammation, and neurological and cardiovascular disorders.&lt;/br&gt; &lt;br&gt;&lt;b&gt;Objective:&lt;/b&gt; This review seeks to critically evaluate recent advancements in lipidomics, particularly concerning membranous nanoparticles such as extracellular vesicles (EVs), and to investigate the analytical potential of time-of-flight secondary ion mass spectrometry (ToF-SIMS) for nanoscale lipid mapping.&lt;/br&gt; &lt;br&gt;&lt;b&gt;Methods:&lt;/b&gt; A comprehensive literature review was conducted, focusing on mass spectrometry (MS)-based lipidomic methodologies. Particular emphasis was placed on studies utilising ToF-SIMS to image lipid distribution and composition in cells and membrane-bound nanoparticles. While traditional MS techniques are proficient in identifying and quantifying lipids, they lack spatial resolution. ToF-SIMS addresses this limitation by enabling in situ molecular imaging at micrometre scales, revealing lipid heterogeneity within biological structures and providing unique insights into membrane architecture and lipid sorting. A comparative evaluation highlights both the strengths (e.g., spatial accuracy) and limitations (e.g., challenges in quantification) of ToF-SIMS in relation to alternative methods.&lt;/br&gt; &lt;br&gt;&lt;b&gt;Conclusions:&lt;/b&gt; ToF-SIMS introduces a critical spatial dimension to lipidomics, bridging conventional bulk analysis with nano-lipidomic imaging. Its integration with complementary techniques holds promise for novel insights into lipid biology, biomarker discovery, and translational applications in diagnostics and drug delivery.&lt;/br&gt;</ns3:p>