Oriented Assembly of Cell-Mimicking Nanoparticles via a Molecular Affinity Strategy for Targeted Drug Delivery

Cell membrane cloaking is an emerging field in drug delivery in which specific functions of parent cells are conferred to newly formed biomimetic vehicles. A growing variety of delivery systems with diverse surface properties have been utilized for this strategy, but it is unclear whether the affinity of membrane-core pairs could guarantee effective and proper camouflaging. In this study, we propose a concise and effective "molecular affinity" strategy using the intracellular domain of transmembrane receptors as "grippers" during membrane coating. Red blood cell (RBC) membranes and cationic liposomes were adopted for fabrication, and a peptide ligand derived from the cytoplasmic protein P4.2 was prepared to specifically recognize the cytoplasmic domain of band 3, a key transmembrane receptor of erythrocytes. Once anchored onto the liposome surface, the P4.2-derived peptide would interact with the isolated RBC membrane, forming a "hidden peptide button", which ensures the right-side-out orientation. The membrane-coated liposomes exhibited an appropriate size distribution around 100 nm and high stability, with superior circulation durations compared with those of conventional PEGylated liposomes. Importantly, they possessed the ability to target Candida albicans by the interaction between the pathogenic fungus and host erythrocytes and to neutralize hemotoxin secreted by the pathogenic fungi. The curative effect of the model drug was thus substantially improved. In summary, the "molecular affinity" strategy may provide a powerful and universal approach for the construction of cell membrane-coated biomaterials and nanomedicines at both laboratory and industrial scales.