The use of liposomes as nanoscale drug delivery systems today is a recognized approach to increasing the effectiveness of treatment and improving the quality of life of cancer patients. Since 1995, when the first liposomal drug Doxil (pegylated, that is, coated with polyethylene glycol (PEG) chains, liposomes with a diameter of about 100 nm with encapsulated antibiotic doxorubicin) appeared the FDA approved about 20 liposome-based drugs for the treatment of oncological and infectious diseases. New technologies for the industrial production of liposomes have appeared. Studies of the interactions of liposomes with blood plasma proteins and the formation of the protein corona remain the focus of attention, as they are aimed at increasing the effectiveness of newly created liposomal preparations. Nevertheless, today the picture of these interactions remains fragmented even for liposomes already used in the clinic. Protein сoronas are often abundant in opsonins, which contribute to the recognition of liposomes by receptors of immunocompetent cells and threaten liposome integrity, as well as cause possible development of hypersensitivity reactions of varying severity in the patient associated with the activation of the complement system. In addition, proteins specific for receptors of non-immune system-associated cells can concentrate on the surface of the corona, which in turn can radically change liposome biodistribution. The formation of a protein corona is determined by the physicochemical properties of the carrier surface, as shown by studies of the interactions of nanoparticles based on polymers and metals, mainly with individual proteins (not with whole plasma). The range of the studied liposomal systems is too narrow to allow drawing conclusions about the patterns of formation of protein corona and their influence on the behavior of liposomes in the body. At the same time, for different drugs, depending on the structure of the molecules, the development of liposomes of different compositions with different physicochemical parameters of the surface is required. To obtain a holistic picture of the relationship between the structure of liposomes and their behavior in the body, a whole complex of studies is needed, combining the analysis of the structure and properties of specific lipid bilayers, the study of the structure of the protein corona of liposomes formed in the blood plasma, and the study of the effect of the corona on the interaction of liposomes with cells of the bloodstream. In the early studies of liposome–protein interactions, the task was to establish a relationship between the amount of plasma protein in the corona and the lifetime of liposomes in the bloodstream. Today, with the help of improved instrumental analysis methods, the study of the corona of nanoparticles and liposomes has reached the level of studying the molecular composition and constructing a mechanistic picture of corona formation. However, only a few works are devoted to the study of the reasons for the formation of a corona of a certain composition on a specific type of liposomes or the effect of the corona on interactions with cells in the bloodstream, on which biodistribution and the final therapeutic effect largely depend. Moreover, the methods the researchers use to isolate liposome–protein complexes are not always reliable, which leads to conflicting results. We propose to use a combination of methods of physicochemical biology for systematic detection of blood plasma proteins, which are most represented in the protein corona of medicinal liposomes of various compositions, to study the patterns of binding of such proteins to liposomes and the effect of this binding on further interactions of liposomes with cells. The objects of the research are liposomes built from mixtures of natural lipids, carrying lipophilic prodrugs in the bilayer. Lipophilic modification of drugs makes it possible to simplify the technology of liposome production with a therapeutically effective drug concentration and to facilitate the intracellular unloading of liposomes. This approach for liposome preparation has been spreading lately. Synthetic lipid molecules in the bilayer significantly affect its physicochemical properties and, as a consequence, the composition of the protein corona. Our group investigated individual plasma proteins in the crown of liposomes with prodrugs using classical biochemistry methods (Kuznetsova and Vodovozova, 2014; Tretyakova 2017). More extensive studies of the protein corona of liposomes with lipophilic prodrugs in the bilayer have not been carried out. The project involves the following set of studies. The selection of liposome compositions stable in human blood plasma, forming a liquid-phase lipid bilayer, which is preferable for the incorporation of lipophilic prodrugs, will be carried out using fluorescence spectroscopy. The use of LC-MS/MS in combination with the methods of classical biochemistry (SDS-PAGE and WB) will give the comprehensive picture of the composition of the protein corona of various liposome designs. A direct comparison of the methods to isolate liposome–protein complexes, which has not been performed previously, will allow us to single out the characteristic features of each of the approaches and choose the one optimal for our tasks. Special attention will be paid to the development of a methodology to study structural organization of the corona using confocal fluorescence microscopy and ELISA. As far as we know, such studies have not been carried out neither for liposomes, nor for any other type of nanoparticles. Taken together, the data obtained will allow establishing the laws of the formation of the protein corona of liposomes with lipophilic prodrugs. The study of interactions of liposome–protein complexes with leukocytes and endothelial cells of blood vessels using cytofluorimetry will make it possible to establish how the composition and structure of the protein corona of liposomes affect the interaction of liposomes with cells.