Directional coating of cell membranes preserves native orientation and prolongs circulation of biomimetic nanocarriers for tumor therapy.

Cell membrane biomimetic delivery system can reduce the toxicity of encapsulated drugs and prolong systemic circulation. However, current studies have shown that cell membrane often undergo inside-out inversion during the coating process, which may weaken or impair their intrinsic functional properties, such as homologous targeting and long circulation in vivo. To address this, we developed a simple and effective directional membrane coating strategy by screening a peptide that specifically targets phosphatidylserine (PS) on the inner side of the cell membrane and modifying it onto the surface of drug-loaded nanocarriers. This approach preserves the native membrane orientation throughout the coating process. Using this strategy, we engineered red blood cell membrane (RBCm) directional coating bufalin (BF) liposomes (BF/Lip-Pep@RBC). The resulting nanocarrier retained CD47 outward display and PS internalization, reduced macrophage uptake by 79.76%, and extended circulation half-life by 2.24-fold compared to non-directional coating controls. In a breast cancer model, BF/Lip-Pep@RBC exhibited potent antitumor efficacy with favorable biosafety. By resolving the critical and long-overlooked issue of membrane orientation loss, this directional coating strategy establishes a broadly applicable and scalable platform for the rational design of functionally intact cell membrane-coated nanomedicines.