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Phosphatidylserine (PS) is the representative of biocompatible anionic phospholipid that is a component of cell membrane. On a molar basis, PS is a relatively minor component of most biofilms. However, given the unique physical and biochemical properties of PS, its physiological importance exceeds its low abundance, which can alter the charge of the phagosome, which in turn can be used to target proteins with polycationic clusters or polybasic domains. PS has a structural role in maintaining cell membrane integrity and affects a variety of neurochemical systems, including dopaminergic and cholinergic systems. In addition, PS is the key to the recruitment and activation of many enzymes and structural components, and it marks important events such as the clearance of apoptotic cells and the internalization of viruses by host cells. When cells undergo apoptosis, a large number of PS located in the inner leaflets of the plasma membrane are transferred to the extracellular membrane (Fig. 1). Exposed PS serves as a specific recognition signal for macrophages to phagocytize apoptotic cells. Nanomaterials containing PS liposomes exhibit immunomodulatory functions in different models of inflammation or deliver agents to specific sites enriched with macrophages.

PS-liposomes mimic apoptotic cell fragments Fig. 1 PS-liposomes mimic apoptotic cell fragments


PS-based anionic liposomes are usually monolayers with a size of 100 nm. The main components of PS liposomes are 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (sodium salt) (DOPS) and 1, 2-dioleyl-Sn-glycerol 3-phosphate choline (DOPC), which are both unsaturated liposomes.

Composition of PS-based anionic liposomes Fig. 2 Composition of PS-based anionic liposomes

Their liquid-gel phase transition temperature is below 0°C, and the unsaturated liposomes have "curly legs", so the loosely wrapped liposomes are formed, affecting the intermolecular interactions and the surface of liposomes). Different molar ratios (DOPS:DOPC) can be prepared depending on the required lipid loading. The amount of negative Zeta potential in liposomes depends on the molar percentage of PS in the preparation .


PS-based anionic liposomes are prepared from lipid mixtures of PS and PC at different molar ratios by thin film hydration method.

The process of thin film hydration method Fig. 3 The process of thin film hydration method

The degree of PS exposure on liposomes is assessed by


The inclusion of PS can lead to preferential recognition of liposomes by macrophages and improve the efficiency of drug encapsulation. As a result of specific or electrostatic interactions between cells and vesicles, charged liposomes containing PS are phagocytosed at a higher rate, thereby facilitating macrophage-targeted drug delivery. Therefore, targeting macrophage PS liposomes has become a promising approach for drug delivery.

PS-based anionic liposomes have been used in host-directed therapy (based on adjusting the host response), utilizing simple PS liposomes to manipulate the immune response, which effectively augments the microbicidal response of macrophages, resulting in a significant reduction of intracellular mycobacterial viability both in single-infected and in M. tuberculosis-HIV–coinfected macrophages in the absence of antigen-specific CD4+ T cells.

Employing PS-based anionic liposomes to mimic the apoptotic cells to attenuate atherosclerosis and reduce the related inflammation through the specific activation and expansion of peritoneal B1a cells followed by increasing the secretion of more reactive IgM, provides a novel treatment strategy for reducing atherosclerosis associated with myocardial infarction and stroke morbidity and mortality. In addition, apoptosis mimicry-based PS liposomes loaded with autoantigens can also help to restore tolerance lost in human autoimmune diabetes, and promote inflammation resolution and angiogenesis to improve myocardial infarct repair.


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  2. Klein M.E.; et al. Towards the development of long circulating phosphatidylserine (PS)- and phosphatidylglycerol (PG)-enriched anti-inflammatory liposomes: is pegylation effective? Pharmaceutics. 2021. 13(2): p. 282.
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  4. Pujol-Autonell I; et al. Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes. PLoS One. 2015. 10(6): p. e0127057.
  5. Rodriguez-Fernandez S; et al. Phosphatidylserine-Liposomes promote tolerogenic features on dendritic cells in human type 1 diabetes by apoptotic mimicry. Front Immunol. 2018. 9: p. 253.

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