Cell Membrane Coating Nanotechnology

Nanoparticle‐based therapeutic, prevention, and detection modalities have the potential to greatly impact how diseases are diagnosed and managed in the clinic. With the wide range of nanomaterials available, the rational design of nanocarriers on an application‐specific basis has become increasingly commonplace. Here, a comprehensive overview is provided on an emerging platform: cell‐membrane‐coating nanotechnology. As a fundamental unit of biology, cells carry out a wide range of functions, including the remarkable ability to interface and interact with their surrounding environment. Instead of attempting to replicate such functions via synthetic techniques, researchers are now directly leveraging naturally derived cell membranes as a means of bestowing nanoparticles with enhanced biointerfacing capabilities. This top‐down technique is facile, highly generalizable, and has the potential to greatly augment existing nanocarriers. Further, the introduction of a natural membrane substrate onto nanoparticles surfaces has enabled additional applications beyond those traditionally associated with nanomedicine. Despite its relative youth, there exists an impressive body of literature on cell membrane coating, which is covered here in detail. Overall, there is still significant room for development, as researchers continue to refine existing workflows while finding new and exciting applications that can take advantage of this developing technology.     

Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine. However, only limited efforts have been dedicated to engineering such camouflage to endow it with optimized or additional properties, in particular properties critical to a “smart” drug delivery system, such as stimuli‐responsive drug release. A pH‐responsive biomimetic “platesome” for specific drug delivery to tumors and tumor‐triggered drug release is described. This platesome nanovehicle is constructed by merging platelet membranes with functionalized synthetic liposomes and exhibits enhanced tumor affinity, due to its platelet membrane–based camouflage, and selectively releases its cargo in response to the acidic microenvironment of lysosomal compartments. In mouse cancer models, it shows significantly better antitumor efficacy than nanoformulations based on a platesome without pH responsiveness or those based on traditional pH‐sensitive liposomes. A convenient way to incorporate stimuli‐responsive features into biomimetic nanoparticles is described, demonstrating the potential of engineered cell membranes as biomimetic camouflages for a new generation of biocompatible and efficient nanocarriers.     

Light‐Triggered Biomimetic Nanoerythrocyte for Tumor‐Targeted Lung Metastatic Combination Therapy of Malignant Melanoma

Red blood cell (RBC) membrane‐cloaked nanoparticles, reserving the intact cell membrane structure and membrane protein, can gain excellent cell‐specific functions such as long blood circulation and immune escape, providing a promising therapy nanoplatform for drug delivery. Herein, a novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability is constructed by embedding bovine serum albumin (BSA) encapsulated with 1,2‐diaminocyclohexane‐platinum (II) (DACHPt) and indocyanine green (ICG) in the targeting peptide‐modified erythrocyte membrane (R‐RBC@BPtI) for enhancing tumor internalization and synergetic chemophototherapy. R‐RBC@BPtI displays excellent stability and high encapsulation efficiency with multiple cores enveloped in the membrane. Benefited from the stealth functionality and targeting modification of erythrocyte membranes, R‐RBC@BPtI can significantly promote tumor targeting and cellular uptake. Under the near‐infrared laser stimuli, R‐RBC@BPtI presents remarkable instability by singlet oxygen and heat‐mediated cleavage so as to trigger effective drug release, thereby achieving deep penetration and accumulation of DACHPt and ROS in the tumor site. Consequently, R‐RBC@BPtI with tumor‐specific targeting ability accomplishes remarkable ablation of tumors and suppressed lung metastasis in vivo by photothermal and chemotherapy combined ablation under phototriggering. This research provides a novel strategy of targeted biomimetic nanoplatforms for combined cancer chemotherapy–phototherapy.     

Recent Advances in Cell Membrane–Camouflaged Nanoparticles for Cancer Phototherapy

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) employs phototherapeutic agents to generate heat or cytotoxic reactive oxygen species (ROS), and has therefore garnered particular interest for cancer therapy. However, the main challenges faced by conventional phototherapeutic agents include easy recognition by the immune system, rapid clearance from blood circulation, and low accumulation in target sites. Cell‐membrane coating has emerged as a potential way to overcome these limitations, owing to the abundant proteins on the surface of cell membranes that can be inherited to the cell membrane–camouflaged nanoparticles. This review summarizes the recent advances in the development of biomimetic cell membrane–camouflaged nanoparticles for cancer phototherapy. Different sources of cell membranes can be used to coat nanoparticles uisng different coating approaches. After cell‐membrane coating, the photophysical properties of the original phototherapeutic nanoparticles remain nearly unchanged; however, the coated nanoparticles are equipped with additional physiological features including immune escape, in vivo prolonged circulation time, or homologous targeting, depending on the cell sources. Moreover, the coated cell membrane can be ablated from phototherapeutic nanoparticles under laser irradiation, leading to drug release and thus synergetic therapy. By combining other supplementary agents to normalize tumor microenvironment, cell‐membrane coating can further enhance the therapeutic efficacy against cancer.     

Platelet Membrane‐Camouflaged Magnetic Nanoparticles for Ferroptosis‐Enhanced Cancer Immunotherapy

Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe₃O₄‐SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non‐inflamed tumors for cancer immunotherapy. Fe₃O₄‐SAS@PLT are built from sulfasalazine (SAS)‐loaded mesoporous magnetic nanoparticles (Fe₃O₄) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate‐cystine antiporter system X_c^? pathway. Fe₃O₄‐SAS @ PLT‐mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe₃O₄‐SAS @ PLT‐mediated ferroptosis could not only induce tumor‐specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe₃O₄‐SAS @ PLT‐mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.     

Enhanced Liposomal Drug Delivery Via Membrane Fusion Triggered by Dimeric Coiled-Coil Peptides

An ideal nanomedicine system improves the therapeutic efficacy of drugs. However, most nanomedicines enter cells via endosomal/lysosomal pathways and only a small fraction of the cargo enters the cytosol inducing therapeutic effects. To circumvent this inefficiency, alternative approaches are desired. Inspired by fusion machinery found in nature, synthetic lipidated peptide pair E4/K4 is used to induce membrane fusion previously. Peptide K4 interacts specifically with E4, and it has a lipid membrane affinity and resulting in membrane remodeling. To design efficient fusogens with multiple interactions, dimeric K4 variants are synthesized to improve fusion with E4-modified liposomes and cells. The secondary structure and self-assembly of dimers are studied; the parallel PK4 dimer forms temperature-dependent higher-order assemblies, while linear K4 dimers form tetramer-like homodimers. The structures and membrane interactions of PK4 are supported by molecular dynamics simulations. Upon addition of E4, PK4 induced the strongest coiled-coil interaction resulting in a higher liposomal delivery compared to linear dimers and monomer. Using a wide spectrum of endocytosis inhibitors, membrane fusion is found to be the main cellular uptake pathway. Doxorubicin delivery results in efficient cellular uptake and concomitant antitumor efficacy. These findings aid the development of efficient delivery systems of drugs into cells using liposome-cell fusion strategies.     

Interfacing the Cell with “Biomimetic Membrane Proteins”

Integral membrane proteins mediate a myriad of cellular processes and are the target of many therapeutic drugs. Enhancement and extension of the functional scope of membrane proteins can be realized by membrane incorporation of engineered nanoparticles designed for specific diagnostic and therapeutic applications. In contrast to hydrophobic insertion of small amphiphilic molecules, delivery and membrane incorporation of particles on the nanometric scale poses a crucial barrier for technological development. In this perspective, the transformative potential of biomimetic membrane proteins (BMPs), current state of the art, and the barriers that need to be overcome in order to advance the field are discussed.     

Membrane Tension–Mediated Growth of Liposomes

Recent years have seen a tremendous interest in the bottom‐up reconstitution of minimal biomolecular systems, with the ultimate aim of creating an autonomous synthetic cell. One of the universal features of living systems is cell growth, where the cell membrane expands through the incorporation of newly synthesized lipid molecules. Here, the gradual tension‐mediated growth of cell‐sized (≈10 µm) giant unilamellar vesicles (GUVs) is demonstrated, to which nanometer‐sized (≈30 nm) small unilamellar vesicles (SUVs) are provided, that act as a lipid source. By putting tension on the GUV membranes through a transmembrane osmotic pressure, SUV–GUV fusion events are promoted and substantial growth of the GUV is caused, even up to doubling its volume. Thus, experimental evidence is provided that membrane tension alone is sufficient to bring about membrane fusion and growth is demonstrated for both pure phospholipid liposomes and for hybrid vesicles with a mixture of phospholipids and fatty acids. The results show that growth of liposomes can be realized in a protein‐free minimal system, which may find useful applications in achieving autonomous synthetic cells that are capable of undergoing a continuous growth–division cycle.     

Hybrid Structures for Surface‐Enhanced Raman Scattering: DNA Origami/Gold Nanoparticle Dimer/Graphene

A combination of three innovative materials within one hybrid structure to explore the synergistic interaction of their individual properties is presented. The unique electronic, mechanical, and thermal properties of graphene are combined with the plasmonic properties of gold nanoparticle (AuNP) dimers, which are assembled using DNA origami nanostructures. This novel hybrid structure is characterized by means of correlated atomic force microscopy and surface‐enhanced Raman scattering (SERS). It is demonstrated that strong interactions between graphene and AuNPs result in superior SERS performance of the hybrid structure compared to their individual components. This is particularly evident in efficient fluorescence quenching, reduced background, and a decrease of the photobleaching rate up to one order of magnitude. The versatility of DNA origami structures to serve as interface for complex and precise arrangements of nanoparticles and other functional entities provides the basis to further exploit the potential of the here presented DNA origami–AuNP dimer–graphene hybrid structures.     

Shuttle‐Mediated Nanoparticle Delivery to the Blood–Brain Barrier

Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood–brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.     

Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions

The zebrafish embryo is a vertebrate well suited for visualizing nanoparticles at high resolution in live animals. Its optical transparency and genetic versatility allow noninvasive, real‐time observations of vascular flow of nanoparticles and their interactions with cells throughout the body. As a consequence, this system enables the acquisition of quantitative data that are difficult to obtain in rodents. Until now, a few studies using the zebrafish model have only described semiquantitative results on key nanoparticle parameters. Here, a MACRO dedicated to automated quantitative methods is described for analyzing important parameters of nanoparticle behavior, such as circulation time and interactions with key target cells, macrophages, and endothelial cells. Direct comparison of four nanoparticle (NP) formulations in zebrafish embryos and mice reveals that data obtained in zebrafish can be used to predict NPs' behavior in the mouse model. NPs having long or short blood circulation in rodents behave similarly in the zebrafish embryo, with low circulation times being a consequence of NP uptake into macrophages or endothelial cells. It is proposed that the zebrafish embryo has the potential to become an important intermediate screening system for nanoparticle research to bridge the gap between cell culture studies and preclinical rodent models such as the mouse.