Cell membrane-derived nanomaterials for biomedical applications

Abstract

The continued evolution of biomedical nanotechnology has enabled clinicians to better detect, prevent, manage, and treat human disease. In order to further push the limits of nanoparticle performance and functionality, there has recently been a paradigm shift towards biomimetic design strategies. By taking inspiration from nature, the goal is to create next-generation nanoparticle platforms that can more effectively navigate and interact with the incredibly complex biological systems that exist within the body. Of great interest are cellular membranes, which play essential roles in biointerfacing, self-identification, signal transduction, and compartmentalization. In this review, we explore the major ways in which researchers have directly leveraged cell membrane-derived biomaterials for the fabrication of novel nanotherapeutics and nanodiagnostics. Such emerging technologies have the potential to significantly advance the field of nanomedicine, helping to improve upon traditional modalities while also enabling novel applications.

Keywords: Biomimetic nanoparticle; Cell membrane; Detoxification; Drug delivery; Imaging; Immunotherapy.

Fig. 1. Cell membrane-based strategies for nanoparticle functionalization

A) Many cellular properties are determined by membrane composition, including the different proteins and glycan structures that are present. B) Examples of different cell membrane-based design strategies for fabricating biomimetic nanoparticles. Single molecule or subunit derivatives of cell membrane glycans and proteins can be used as functional ligands. Biomacromolecule components of the cell membrane, such as proteins and glycans, can be used to add specific functionalities. Further, entire cell membranes can be leveraged either directly as vesicular structures or as the coating material for a nanoparticulate core.

Fig. 2. Sugar-functionalized nanoparticles

A) Schematic of a nanoparticle-based vaccine formulation using mannose to target dendritic cells for cancer immunotherapy. B) Imaging of tumors on day 20 after tumor inoculation demonstrates efficacy of the different nanoformulation variants. C) Schematic of magnetic glyconanoparticles for use in the detection of cancer cells with different carbohydrate binding affinities. D) Linear discriminant analysis plot demonstrating the ability to fully differentiate 10 different cancer cell lines bound with the nanoformulations according to their magnetic resonance signature. A, B adapted with permission from [42]. Copyright Elsevier, 2013. C, D adapted with permission from [55]. Copyright American Chemical Society, 2010.

Fig. 3. Peptide-functionalized nanoparticles

A) Schematic of particle functionalization with CD47-derived “self” peptide for suppressing phagocytosis. B) Total fluorescence quantification by in situ tumor imaging demonstrates increased uptake over time of the peptide-functionalized nanoformulation. C) Schematic of liposome-polycation-DNA nanoparticles incorporated with immunological adjuvant and the HER2/neu-derived peptide being taken up across the cell membrane for anticancer vaccination. D) Survival of mice over 80 days after tumor challenge demonstrates prophylactic efficacy of different nanoformulations. A, B adapted with permission from [58]. Copyright American Association for the Advancement of Science, 2013. C, D adapted with permission from [75]. Copyright Elsevier, 2012.

Fig. 4. Glycan-functionalized nanoparticles

A) Schematic of glycan-functionalized gold nanoparticles for the colorimetric detection of viruses. B) Colorimetric response after incubation of viruses with the nanoformulations can be used to distinguish each strain based on its reactions with the different glycans. Adapted with permission from [95]. Copyright Elsevier, 2017.

Fig. 5. Protein-functionalized nanoparticles

A) Schematic of hyaluronidase-functionalized drug loaded nanoparticles for enhanced tumor drug delivery. B) Tumor growth kinetics for 20 days after inoculation demonstrates antitumor activity of the nanoformulations. C) Survival curve demonstrates therapeutic efficacy of the nanoformulations over time. Adapted with permission from [114]. Copyright American Chemical Society, 2016.

Fig. 6. Natural membrane vesicles

A) Schematic demonstrating workflow for the fabrication and subsequent administration of siRNA-loaded exosomes for brain-targeted delivery. B) Quantification of BACE1 protein and mRNA expression as well as β-amyloid concentration demonstrates significant knockdown efficacy for the nanoformulation. C) Schematic demonstrating the fabrication of leukosomes via the isolation of membrane proteins followed by reconstitution with synthetic lipids. D) Intravital microscopy images demonstrate preferential accumulation at the site of inflamed tissue over time. Scale bars = 50 μm. A, B adapted with permission from [131]. Copyright Nature Publishing Group, 2011. C, D adapted with permission from [150]. Copyright Nature Publishing Group, 2016.

Fig. 7. Cell membrane-coated nanoparticles

A) Schematic of RBC membrane-coated nanoparticle fabrication via an extrusion method. B) Monitoring of fluorescent nanoparticle signal over time demonstrates enhanced circulation for the membrane-coated nanoparticles. C) Schematic of the different applications towards which platelet membrane-coated nanoparticles can be applied, including targeting of damaged vasculature and pathogen binding. D) Platelet membrane-coated nanoparticles do not target intact endothelium (top), but show significant binding when the endothelial layer is removed (bottom). Scale bar = 200 μm. E) Methicillin-resistant Staphylococcus aureus (top) shows significant binding when incubated with platelet membrane-coated nanoparticles (bottom). Scale bar = 1 μm. A,B adapted with permission from [206]. National Academy of Sciences, 2011. C–E adapted with permission from [229]. Nature Publishing Group, 2015.