One of the most widely used approaches for manipulating lipid composition at the plasma membrane level is the use of β-cyclodextrin-based methods , as illustrated in Figure . β-Cyclodextrins are cyclic oligosaccharides with a hydrophobic cavity that can encapsulate lipid molecules, making them highly effective for lipid delivery or cholesterol removal at the plasma membrane. For example, β-cyclodextrin can be pre-loaded with a specific lipid of interest, such as cholesterol or sphingomyelin, and subsequently incubated with cells. This process facilitates the targeted delivery of these lipids to the outer leaflet of the plasma membrane, potentially disrupting the asymmetry of lipid species such as PI(4,5)P 2 , which is exclusively located in the inner leaflet. In addition to lipid delivery, (methyl-)β-cyclodextrin can also be employed to extract cholesterol from the plasma membrane outer leaflet. However, while effective, this lipid extraction approach has limitations that can lead to unintended alterations in membrane composition and induce cytotoxic effects. This method has been employed to manipulate cholesterol content in the plasma membrane. It is well established that altering cholesterol levels positively influences the recruitment and translocation of FGF2 . In contrast, little is known about manipulating SM and PI(4,5)P 2 levels in cells influencing the mechanisms underlying FGF2 secretion. Sphingomyelin is predominantly located in the outer leaflet of the plasma membrane, where it plays essential roles in maintaining membrane stability, organizing lipid domains, and mediating signaling processes. SM scramblases can translocate SM across the bilayer. Still, their activity is calcium-dependent, which may expose cytosolic leaflet lipids to the outer leaflet and it is coupled with the enzymatic action of sphingomyelinase in the inner leaflet. This enzyme converts SM into ceramide, introducing metabolic changes that complicate the study of SM dynamics. The single-cell injection method is a precise and promising alternative , which could deliver SM directly into the inner leaflet. This approach would bypass scramblase activity, offering a controlled environment for investigating lipid redistribution. However, the physical penetration of the cell membrane can cause stress or damage to the cell, potentially affecting its viability or normal function. Furthermore, this approach enables the enrichment of SM in various membrane organelles, which could potentially alter normal cellular functions. On the other hand, Phosphatidylinositol 4,5-bisphosphate is predominantly located in the inner leaflet of the plasma membrane, where it functions as a critical signaling lipid and regulator of membrane dynamics . Its intracellular localization presents opportunities for simple external intervention to disrupt lipid asymmetry. One effective strategy involves the targeted delivery of PI(4,5)P₂ micelles directly within the cell medium , as illustrated in Figure . These micelles have a high partition coefficient and will efficiently incorporate into the outer leaflet of the plasma membrane.