Abstract
Cell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. However, the integrity of the cell membrane coating on NPs, a key metrics related to the quality of these biomimetic-systems and their resulting biomedical function, has remained largely unexplored. Here, we report a fluorescence quenching assay to probe the integrity of cell membrane coating. In contradiction to the common assumption of perfect coating, we uncover that up to 90% of the biomimetic NPs are only partially coated. Using in vitro homologous targeting studies, we demonstrate that partially coated NPs could still be internalized by the target cells. By combining molecular simulations with experimental analysis, we further identify an endocytic entry mechanism for these NPs. We unravel that NPs with a high coating degree (≥50%) enter the cells individually, whereas the NPs with a low coating degree (<50%) need to aggregate together before internalization. This quantitative method and the fundamental understanding of how cell membrane coated NPs enter the cells will enhance the rational designing of biomimetic nanosystems and pave the way for more effective cancer nanomedicine.
Highlights
Cell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific molecular recognition and cell targeting
If one considers biomimetic NPs, the loss of lipid shell integrity could affect their biomedical functionalities, such as cargo leakage in drug delivery systems[12], undesired biomolecules adsorption occurred in physiological fluids[13,14], changes in the NPs’ mechanical properties and last but not least, alterations in the molecular affinity of the membranes[15]
Existing methods for confirming a successful cell membrane coating have largely relied on transmission electron microscope (TEM) observation, dynamic light scattering (DLS) measurement, evaluation of zeta potential, colloidal stability test in phosphatebuffered saline (PBS) or fetal bovine serum (FBS), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis[16,17,18,19,20,21]
Summary
Cell membrane coated nanoparticles (NPs) have recently been recognized as attractive nanomedical tools because of their unique properties such as immune escape, long blood circulation time, specific molecular recognition and cell targeting. Cell membrane-coated NPs inherently mimic the surface properties of the source cells and acquire many unique characteristics, such as superior biocompatibility, decreased uptake by macrophage cells, prolonged circulation lifetimes, and enhanced tumor penetration[2,3,4,5] Based on these advantages, a wide variety of cell types including red blood cells (RBCs), platelets, white blood cells, cancer cells, stem cells and even bacteria, have been employed as sources of cell membranes to coat synthetic NPs6,7. In addition to the reserved membrane proteins, it is essential to investigate whether the integrity of the cell membrane can be replicated onto the biomimetic NPs. Existing methods for confirming a successful cell membrane coating have largely relied on transmission electron microscope (TEM) observation, dynamic light scattering (DLS) measurement, evaluation of zeta potential, colloidal stability test in phosphatebuffered saline (PBS) or fetal bovine serum (FBS), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis[16,17,18,19,20,21].
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