Engineered Cell Membrane-Camouflaged Nanomaterials for Biomedical Applications

Abstract

Recent strides in nanomaterials science have paved the way for the creation of reliable, effective, highly accurate, and user-friendly biomedical systems. Pioneering the integration of natural cell membranes into sophisticated nanocarrier architectures, cell membrane camouflage has emerged as a transformative approach for regulated drug delivery, offering the benefits of minimal immunogenicity coupled with active targeting capabilities. Nevertheless, the utility of nanomaterials with such camouflage is curtailed by challenges like suboptimal targeting precision and lackluster therapeutic efficacy. Tailored cell membrane engineering stands at the forefront of biomedicine, equipping nanoplatforms with the capacity to conduct more complex operations. This review commences with an examination of prevailing methodologies in cell membrane engineering, spotlighting strategies such as direct chemical modification, lipid insertion, membrane hybridization, metabolic glycan labeling, and genetic engineering. Following this, an evaluation of the unique attributes of various nanomaterials is presented, delivering an in-depth scrutiny of the substantial advancements and applications driven by cutting-edge engineered cell membrane camouflage. The discourse culminates by recapitulating the salient influence of engineered cell membrane camouflage within nanomaterial applications and prognosticates its seminal role in transformative healthcare technologies. It is envisaged that the insights offered herein will catalyze novel avenues for the innovation and refinement of engineered cell membrane camouflaged nanotechnologies.

Keywords: active targeting; biomedical applications; cell membrane-camouflaged nanomaterials; engineered cell membrane; long circulation time.

Figure 1

Schematic of engineered cell membrane-camouflaged nanomaterials. The lentivirus in Figure 1 was drawn by the Figdraw 2.0 (https://www.figdraw.com, accessed on 25 December 2023).

Figure 2

Construction of a nano platform for insertion of melittin into cell membranes. (A) The membrane of MΦ can be used as a coating material to divert PLA2 from its intended target cell. (B) A molecular ion peak was identified at m/z = 491.3, which corresponds to the theoretical molecular weight of MJ−33. This indicates that MJ−33 was successfully loaded into the nanoparticle formulations. (C) While free MJ−33 was found to be toxic to macrophages, MΦ−NP(L&K) containing the same amount of MJ−33 was non−toxic. (MΦ: macrophages; AP: acute pancreatitis; PLA2: phospholipase A2; PLGA: polylactic acid−co−glycolic acid; MJ−33: PLA2 inhibitor). Reprinted from [29] with permission from Springer Nature, open access, copyright 2021.

Figure 3

Construction of HM−NPs@G. (A) Methods based on cancer cell–mitochondria hybrid membrane−camouflaged Gboxin−encapsulated ROS−responsive polymeric nanoparticles. (B) TEM images showing the core–shell structure of the developed HM−NPs@G. Scale bar  =  50 nm. (C) CLSM images of the successful fusion of CM and MM. Scale bar = 20 μm. (D) Western blotting analysis of cancer membrane and mitochondria membrane special targeting−related key proteins. (E) Size distribution of NPs@G (without membrane coating) and HM−NPs@G. (TEM: transmission electron microscope; PEG−PHB: poly(ethylene glycol)-poly(4-(4,4,5,5-Tetramethyltetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate); MM: mitochondria membrane; CM: cancer membrane; HM: hybrid membrane; EpCAM: epithelial cell adhesion molecule). Reprinted from [33] with permission from Springer Nature, open access, copyright 2023.

Figure 4

Development of direct chemical modification. (A) BSA−TCO, OVA−oD1, and LYSO−Az were reacted with different fluorophore−modified bioorthogonal compounds. (B) SDS−PAGE analysis result of orthogonal labeling of three different proteins based on DFC, SPAAC, and IEDDA reactions. (C) Distinguishing three different cell groups using EGFR and HER2 antibodies. (D) Fluorescence signal analysis indicates that A549 (TCO) can only be modified by the IEDDA reaction. (BSA: bovine serum albumin; TCO: trans−cyclooctene; Tz: Phenyl−methyl−tetrazine; Cy5: fluorescent dyes; OVA: ovalbumin; oD1: o−dione; SDS−PAGE: sodium dodecyl sulfate–polyacrylamide gel electrophoresis; FuA: furan−2 (3H)−one substrate; TAMRA: Carboxytetramethylrhodamine; LYSO: lysozyme; Az: azide; DBCO: Dibenzocyclooctyne; FITC: Fluorescein Isothiocyanate; DFC: o−dione and furan−2 (3H)−one cycloaddition; SPAAC: strain−promoted azide–alkyne click reaction; IEDDA: inverse−electron−demand Diels–Alder reaction). Reprinted from [43] with permission from Springer Nature, copyright 2023.

Figure 5

Development of metabolic glycan labeling. (A) The synergism of M1 Exo-Ab. (B) Fluorescence imaging of pristine M1 Exo and M1 Exo-N₃ after incubation with DBCO-Cy5 confirmed M1 Exo carried azide groups on their surface. (C) Release profiles of total Ab from M1 Exo-Ab at different pHs (6.5 and 7.4) demonstrating the selective cleavage of the benzoic-imine bond. (M1 Exo-Ab: exosome nanobioconjugates; MΦ: macrophages; aCD47: anti-CD47 antibody; SIRPα: signal regulatory proteins; Ab: antibody). Reprinted from [50] with permission from Wiley, copyright 2019.

Figure 6

Development of genetic engineering. (A) The CXCR4-CMVs possess natural membrane surface characteristics. (B) After transfection with a lentivirus vector encoding the CXCR4/GFP chimeric protein, the fluorescence expression of membrane CXCR4 protein (red) in the transfection group’s 3T3 cells was significantly higher than that of the wild-type 3T3 cells. Scale bar = 50 µm. And a higher magnification. Scale bar = 20 µm. (C) The results of the RT-PCR analysis showed a significant increase in CXCR4 mRNA levels in the transfected group compared to the vehicle group (*** p < 0.001, n = 3). (D) The Western blot analysis revealed a significant increase in CXCR4 protein expression levels of CXCR4-3T3 and CXCR4-CMVs after lentivirus transfection. (RT-PCR: reverse transcription–polymerase chain reaction; CMVs: cell membrane vesicles; SDF-1: stromal cell-derived factor-1; DAPI: 4′,6-diamidino-2-phenylindole; Dil: 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate). Reprinted from [60] with permission from Wiley, open access, copyright 2021.

Figure 7

(A) Schematic illustration of overexpressing scFv of the EGFR antibody on the surface of the Jurkat cell membrane and cell membrane-camouflaged MNs. JE-CM-MNs were shown to maintain specific recognition of EGFR-positive CTCs. Scale bar = 5 µm. (ScFv: single-chain variable fragment; JE-CM: chimeric antibody membrane). Reprinted from [121] with permission from Wiley, copyright 2023. (B) The method of preparing HDFGFR4/CMMNPs. (FGFR4: fibroblast growth factor receptor 4). Reprinted from [127] with permission from ACS Applied Materials & Interfaces, copyright 2023.

Figure 8

(A) The fabrication of CD47@CCM-Lap-CuS NPs. Under laser irradiation, a photothermal therapeutic effect is produced on the tumor tissue and Lap is released into breast cancer cells to generate H₂O₂. (Lap: β-Lapachone; NQO1: NAD (P) H:quinone oxidoreductase). Reprinted from [108] with permission from ACS Applied Materials & Interfaces, copyright 2023. (B) Schematic of structure of M-αPD-L1 overexpressing membrane-coated BTO nanoparticles. Following the delivery of M@BTO into the tumor microenvironment, the masking domain of the MMP2-sensitive peptide is cleaved and the binding domain of the antibody is exposed to exert the effect of blocking the PD-L1 receptor. Under US conditions, the BTO nanoparticles generate ROS to induce immunogenic cell death. (MMP2: matrix metallopeptidase 2; US: ultrasound; ROS: reactive oxygen species; PD-1: programmed death 1; PD-L1: programmed death ligand 1; HIF-1α: hypoxia-inducible factor 1-alpha; αPD-L1: anti-PD-L1 antibodies; HMGB1: high-mobility group box-1 protein; IFN-γ: interferon γ; HSP70: heatshockprotein70; CRT: calreticulin). Reprinted from [110] with permission from Wiley, copyright 2023. (C) Scheme of preparation of U-ACPT@MM. Upon irradiation at 808 nm, the short-wavelength UV emission of UCNPs breaks the photolabile linker, releasing ACPT, which is incorporated into the membranes of tumor cells. (ACPT: 9-aminocamptothecin; LDH: lactate dehydrogenase). Reprinted from [77] with permission from ELSEVIER, copyright 2023. (D) The process of synthesizing typical NPs involves a combination of immunotherapy and PDT. (FM: cytomembrane; DC: dendritic cell; TCPP: Tetrakis (4-carboxyphenyl) porphyrin; PCN: porous coordination network). Reprinted from [143] with permission from Wiley, copyright 2019.

Figure 9

(A) The membrane from the SpyCatcher-expressing cells can be coated onto nanoparticle cores to create CNPs. These CNPs can then be functionalized with SpyTag-labeled ligands to enhance their functionality in a modular way. Reprinted from [89] with permission from Springer Nature, copyright 2023. (B) Schematic illustration of using adenovirus containing GFP and Lamp2b RVG to induce NSCs to express specific Lamp2b. (Lamp2b: glycoprotein 2b; NSC: neural stem cell; Bex: bexarotene; RVG: rabies viral glycoprotein). Reprinted from [102] with permission from American Chemical Society, copyright 2023.

Figure 10

The LNP was loaded with synthetic ADAR1-siRNA with high encapsulation efficiency. Afterward, a layer of GECM with PD1 overexpression was coated onto the siAdar1-loaded LN. (siAdar1-LNP@mPD1: a layer of GECM with PD1 overexpression was coated onto the siAdar1-loaded LNP; siAdar1: small interfering RNA against ADAR1; LNP: lipid nanoparticle; ADAR1: adenosine deaminases acting on RNA; ICB: immune checkpoint blockade; GECMs: genetically engineered cell membranes; siAdar1-LNP@mPD1: siAdar1-loaded LNP was coated with a layer of the GECM with PD1 overexpression; siAdar1-LNP: LNPs to deliver ADAR1-targeted siRNA; MHC: major histocompatibility complex). Reprinted from [99] with permission from Cell Press, copyright 2023.