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Abstract Liposomes are highly effective nanocarriers for encapsulating and delivering a wide range of therapeutic cargo. While advancements in liposome design have improved several pharmacological characteristics, an important area that would benefit from further progress involves cellular targeting and entry. In this concept article, we will focus on recent progress utilizing strategies including reversible covalent bonding and caging groups to activate liposomal cell entry. These approaches take advantage of advancements that have been made in complementary fields including molecular sensing and chemical biology and direct this technology toward controlling liposome cell delivery properties. The decoration of liposomes with groups including boronic acids and cyclic disulfides is presented as a means for driving delivery through reaction with functional groups on cell surfaces. Additionally, caging groups can be exploited to activate cell delivery only upon encountering a target stimulus. These approaches provide promising new avenues for controlling cell delivery in the development of next‐generation liposomal therapeutic nanocarriers. 

Abstract Liposomes are effective therapeutic delivery nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of therapeutics. Two primary areas in which improvement is needed for liposomal drug delivery is to enhance the ability to infiltrate cells and to facilitate derivatization of the liposome surface. Herein, we report a liposome platform incorporating a cyclic disulfide lipid (CDL) for the dual purpose of enhancing cell entry and functionalizing the liposome membrane through thiol‐disulfide exchange. In order to accomplish this,CDL‐1andCDL‐2, composed of lipoic acid (LA) or asparagusic acid (AA) appended to a lipid scaffold, were designed and synthesized. A fluorescence‐based microplate immobilization assay was implemented to show that these compounds enable convenient membrane decoration through reaction with thiol‐functionalized small molecules. Additionally, fluorescence microscopy experiments indicated dramatic enhancements in cellular delivery when CDLs were incorporated within liposomes. These results demonstrate that multifunctional CDLs serve as an exciting liposome system for surface decoration and enhanced cellular delivery. 

Abstract Liposomes are effective therapeutic nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of drugs and diagnostic agents. A primary area in which improvement is needed for liposomal drug delivery is to maximize the delivery of these nanocarriers to cells. Cell membrane glycans provide exciting targets for liposomal delivery since they are often densely clustered on cell membranes and glycan overabundance and aberrant glycosylation patterns are a common feature of diseased cells. Herein, we report a liposome platform incorporating bis‐boronic acid lipids (BBALs) to increase valency in order to achieve selective saccharide sensing and enhance cell surface recognition based on carbohydrate binding interactions. In order to vary properties, multiple BBALs (1 a–d) with variable linkers in between the binding units were designed and synthesized. Fluorescence‐based microplate screening of carbohydrate binding showed that these compounds exhibit varying binding properties depending on their structures. Additionally, fluorescence microscopy experiments indicated enhancements in cellular association when BBALs were incorporated within liposomes. These results demonstrate that multivalent BBALs serve as an exciting glycan binding liposome system for targeted delivery.