Chemistries on the inner leaflet of the cell membrane

The cell membrane, characterized by its inherent asymmetry, functions as a dynamic barrier that regulates numerous cellular activities. This Highlight aims to provide the chemistry community with a comprehensive overview of the intriguing and underexplored inner leaflet, encompassing both fundamental biology and emerging synthetic modification strategies. We begin by describing the asymmetric nature of the plasma membrane, with a focus on the distinct roles of lipids, proteins, and glycan chains, highlighting the composition and biofunctions of the inner leaflet and the biological mechanisms that sustain membrane asymmetry. Next, we explore chemical biological strategies for engineering the inner leaflet, including genetic engineering, transmembrane peptides, and liposome fusion-based transport. In the perspective section, we discuss the challenges in developing chemistries for the inner leaflet of the cell membrane, aiming to inspire researchers and collaborators to explore this field and address its unanswered biological questions.