Long-Chain Poly-d-Lysines Interact with the Plasma Membrane and Induce Protective Autophagy and Intense Cell Necrosis

Polylysines have been frequently used in drug delivery and antimicrobial and cell adhesion studies. Because of steric hindrance, chirality plays a major role in the functional difference between poly-l-lysine (PLL) and poly-d-lysine (PDL), especially when they interact with the plasma membranes of mammalian cells. Therefore, it is speculated that the interaction between chiral polylysines and the plasma membrane may cause different cellular behaviors. Here, we carefully investigated the interaction pattern of PLL and PDL with plasma membranes. We found that PDL could be anchored onto the plasma membrane and interact with the membrane lipids, leading to the rapid morphological change and death of A549 cells (a human lung cancer cell line) and HPAEpiCs (a human pulmonary alveolar epithelial cell line). In contrast, PLL exhibited good cytocompatibility and was not anchored onto the plasma membranes of these cells. Unlike PLL, PDL could trigger protective autophagy to prevent cells in a certain degree, and the PDL-caused cell death occurred via intense necrosis (featured by increased intracellular Ca²⁺ content and plasma membrane disruption). In addition, it was found that the short-chain PDL with a repeat unit number of 9 (termed DL9) could locate in lysosomes and induce autophagy at high concentrations, but it could not elicit drastic cell death, which proved that the repeat unit number of polylysine could affect its cellular action. This research confirms that the interaction between chiral polylysines and the plasma membrane can induce autophagy and intense necrosis, which provides guidance for the future studies of chiral molecules/drugs.