Homologous-adhering/targeting cell membrane- and cell-mediated delivery systems: a cancer-catch-cancer strategy in cancer therapy

Abstract

Low tumor enrichment remains a serious and urgent problem for drug delivery in cancer therapy. Accurate targeting of tumor sites is still a critical aim in cancer therapy. Though there have been a variety of delivery strategies to improve the tumor targeting and enrichment, biological barriers still cause most delivered guests to fail or be excreted before they work. Recently, cell membrane-based systems have attracted a huge amount of attention due to their advantages such as easy access, good biocompatibility and immune escape, which contribute to their biomimetic structures and specific surface proteins. Furthermore, cancer cell membrane-based delivery systems are referred to as homologous-targeting function in which they exhibit significantly high adhesion and internalization to homologous-type tumor sites or cells even though the exact mechanism is not entirely revealed. Here, we summarize the sources and characterizations of cancer cell membrane systems, including reconstructed single or hybrid membrane-based nano-/microcarriers, as well as engineered cancer cells. Additionally, advanced applications of these cancer cell membrane systems in cancer therapy are categorized and summarized according to the components of membranes. The potential factors related to homologous targeting of cancer cell membrane-based systems are also discussed. By discussing the applications, challenges and opportunities, we expect the cancer cell membrane-based homologous-targeting systems to have a far-reaching development in preclinic or clinics.

Keywords: cancer therapy; cell membrane; delivery system; homologous targeting; hybrid membrane.

Graphical abstract

Figure 1.

Illustration of preparation of cancer cell membrane-based systems. (A) Preparation of membrane-coated systems by membrane extrusion or ultrasonication. The membrane extrusion method is generally considered to provide better regulation of the particle size of the systems and better homogeneity. (B) Preparation of membrane-coated or cell-based systems by in situ growth or electroporation methods. (C) Cancer cell membrane-based systems prepared by grafting some functional substances onto the membrane surface through covalent bonds. These surface-grafted substances can be delivered to homologous tumor sites. (D) Components and hybrid detections of obtained membrane systems, including Western blotting and FRET methods.

Figure 2.

Illustration of homologous targeting of cell membrane-based micro-/nano-size particles.

Figure 3.

Homologous targeting of AuNP@CCM is regulated by integrin. (A) Representative annotated DFM images of HeLa cells treated by AuNPs with different coatings. Scale bar = 10 μm. (B) Cellular internalization pathways of AuNP@CCM with treatments of different endocytic inhibitors. (C) Illustration of lipid raft and integrin on the cell membrane and count of internalized AuNP@CCMs with/without RGD treatment. (D) Annotated DFM images and uptake of A549 cells, HeLa cells, MCF-7 cells, and human umbilical mesenchymal stem cells (HUMSC) treated by AuNP@CCM. (E) Expression levels of integrin α_vβ₃ by flow cytometry and Western blot. (F) Annotated DFM images and count of plasmonic spots of HeLa cells and HUMSC pretreated with siRNA or cilengitide. Scale bar = 10 μm [96]. Copyright 2020, American Chemical Society.

Figure 4.

Illustration of the advantages of cell membrane-biomimetic nanoparticles and their application on targeting recognition of source cancer cells. (A) Main advantages of the cancer cell membrane system. (B) Illustration of preparation procedure of MCF-7 cell membrane−biomimetic nanoparticles. (C) Cellular uptake of MCF-7 cell membrane−biomimetic nanoparticles by different cells. (D) Mean fluorescence intensity of different cells after co-culturing with MCF-7 cell membrane−biomimetic nanoparticles [54]. Copyright 2016, American Chemical Society.

Figure 5.

The immune escape and homologous selectivity of cancer cell membrane-based systems. (A) Confocal laser scanning microscope (CLSM) images and flow cytometry analysis of RAW 264.7 after the treatment of PFT, PFTT and PFTT@CM, respectively. Scale bar = 20 μm. (B) CLSM images of several cells after being treated with PFTT@CM, respectively. Scale bar = 20 μm [58]. Copyright 2022, Elsevier Ltd. (C) Magnetic resonance imaging and relative tumor MR signal intensity of mice after treatments of the membrane-coated magnetic nanoparticles Fe₃O₄@M-LH and the magnetic nanoparticles Fe₃O₄@PEG at different time points, respectively (***P < 0.001, ****P < 0.0001) [117]. Copyright 2023, the Authors, under exclusive license to Springer Science Business Media, LLC, part of Springer Nature.

Figure 6.

Applications of hybrid systems of cancer cell membranes and other membranes on cancer therapies. (A) Illustration of TME drug delivery system SGNPs for targeted chemotherapy of gliomas. (B) Cellular uptake of SGNPs by neuron cells (HT22), astrocyte (HMC3), and mouse gliomas cells (GL261). (C) CLSM images of cellular internalization of C6-loaded NPs. (D) Biodistribution of IR-780-loaded NPs in the tumors and main organs from heterotopic glioma models and orthotopic glioma models [127]. Copyright 2023, Elsevier Ltd. (E) Illustration of preparation of hybrid membrane-coated NPs and images showing membrane extraction process. (F) In vivo anti-tumor effect of various samples (I: PBS, II: Free PTX, III: PLGA-PTX NPs, IV: PTX-PLGA@RAW NPs, V: PTX-PLGA@143B NPs, VI: PTX-PLGA@[143B-RAW] NPs). (*P < 0.05, **P < 0.01) [143]. Copyright 2021, Dove Medical Press Ltd.

Figure 7.

Bacteria and bacteria-based hybrid membrane systems for cancer therapies. (A) Illustration of the preparation process and motility of the microrockets [157]. Copyright 2019, Elsevier B.V. (B) Illustration of preparation of HM-NPs [159]. Copyright 2022, Springer Nature Limited. (C) In vitro and in vivo expression of CD80 and CD86 suggesting HM-NPs with the capacity to promote DC maturation [132]. Copyright 2021, the American Association for the Advancement of Science. (D) Illustration of MGTe to realize synergistic radiotherapy sensitization and immunotherapy enhancement for breast cancer eradication. (E) Time-dependent Te element analysis by ICP-MS in plasma within 48 h after GTe or MGTe intravenous injection. (F) Biodistribution of Te element after 48-h intravenous administration with GTe or MGTe. (G) Tumor volumes of 4T1-bearing mice with different treatments. (H) Survival curves of unilateral 4T1-bearing mice after various treatments [133]. Copyright 2022, Elsevier Ltd.

Figure 8.

Cancer cells as carriers for homologous cancer therapy. (A) Illustration of preparation of cryo-shocked cells delivery system (defined as LNT) from A549 cells and its application in cancer treatment. (B) Representative cell structure images, size and SEM images of LNT and live A549 cells. Scale bar for CLSM image = 50 μm, and scale bar for SEM images = 50 μm (top) or 5 μm (bottom), respectively. (C) Fluorescence images of isolated lungs and CLMS images after treatment with DiD-labeled liposomes and liposome-loaded LNT for 6 h. Scale bar = 50 μm [112]. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC by-NC). Copyright 2024, The American Association for the Advancement of Science. (D) Illustration of the procedure to prepare LNT cells from AML cells. (E) Fluorescence images of bone isolated 6 h after injection of cy5.5-labeled live C1498 cells, LNT C1498 cells, and paraformaldehyde-fixed C1498 cells. (F) Plasma Dox concentration after intravenous injection of free Dox and Dox-loaded LNT cell [72]. Distributed under a CC by-NC. Copyright 2020, The American Association for the Advancement of Science.