Overcoming Biological Barriers in Cancer Therapy: Cell Membrane-Based Nanocarrier Strategies for Precision Delivery

Abstract

Given the unique capabilities of natural cell membranes, such as prolonged blood circulation and homotypic targeting, extensive research has been devoted to developing cell membrane-inspired nanocarriers for cancer therapy, while most focused on overcoming one or a few biological barriers. In fact, the journey of nanosystems from systemic circulation to tumor cells involves intricate processes, encompassing blood circulation, tissue accumulation, cancer cell targeting, endocytosis, endosomal escape, intracellular trafficking to target sites, and therapeutic action, all of which pose limitations to their clinical translation. This underscores the necessity of meticulously considering these biological barriers in the design of cell membrane-mimetic nanocarriers. In this review, we delineate the functions and applications of diverse types of cell membranes in nanocarrier systems. We elaborate on the biological hurdles encountered at each stage of the biomimetic nanoparticle's odyssey to the target, and comprehensively discuss the obstacles imposed by the tumor microenvironment for precise delivery. Subsequently, we systematically review contemporary cell membrane-based strategies aimed at overcoming these multi-level biological barriers, encompassing hybrid cell membrane (HCM) camouflage, tumor microenvironment remodeling, endosomal/lysosomal escape, multidrug resistance (MDR) reversal, optimization of nanoparticle physicochemical properties, and so on. Finally, we outline potential strategies to accelerate the development of cell membrane-inspired precision nanocarriers and discuss the challenges that must be addressed to enhance their clinical applicability. This review serves as a guide for refining the study of cell membrane-mimetic nanosystems in surmounting in vivo delivery barriers, thereby significantly contributing to advancing the development and application of cell membrane-based nanoparticles in cancer delivery.

Keywords: anti-tumor; biological barriers; cell membrane-mimetic; delivery efficiency; nanodelivery system.

Graphical abstract

Figure 1

Various endogenous cells used to prepare cell membrane-based nanovectors.

Figure 2

Biological barriers encountered by nanovectors during intravenous delivery.

Figure 3

Schematic depiction of four primary strategies employed by cell membrane-based nanovectors to overcome multi-level biological barriers and improve targeted drug delivery for cancer treatment: (i) extension blood half-time and augment tumor targeting relying on the coating layer of hybrid cell membrane; (ii) overcoming tumor barriers via remodeling tumor environment, and decorating with TPPs; (iii) overcoming cell barriers through avoiding lysosomal destruction, optimizing the endocytosis pathway and reversing MDR; (iv) optimization the physicochemical properties of nanoparticles.

Figure 4

Schematic diagram and advantageous study of leutusome integrating plasma membrane components of leukocytes and tumor cells in enhanced solid tumor homing. (A) Schematic presentation of composite LTM-PTXL. (B) TEM images of PTX-loaded liposomal nanoparticles. (C) In vitro cytotoxicity of PTX-loaded liposomal nanoparticles at various concentrations on HN12 cells after 24 h incubation. **indicates p<0.01 (n=6). (D) Leukocyte membrane helps reduce the uptake of nanoparticles by monocytes and neutrophils in the blood. * Indicates p<0.05 and **indicates p<0.01 (n=4). (E) Relative tumor volume growth was monitored over the treatments. (F) Tumor tissue apoptosis was recorded after the various treatments. NS, not significant; **indicates p<0.01, and ***indicates p<0.001 (n=6). Adapted from He H, Guo C, Wang J et al. Leutusome: a biomimetic nanoplatform integrating plasma membrane components of leukocytes and tumor cells for remarkably enhanced solid tumor homing. Nano Lett. 2018;18(10):6164–6174. Copyright 2018 American Chemical Society.

Figure 5

Schematic diagram and advantageous study of Col-M@AuNCs/Dox for enhancing tumor penetration and synergistic therapy in pancreatic cancer. (A) Preparation process of Col-M@AuNCs/Dox. (B) Schematic representation of Col-M@AuNCs/Dox for improved intratumoral penetration, complete tumor destruction, and combined treatment and monitoring through ECM degradation. (C) Live/dead staining images of BxPC3 cells after treatment with the different preparations. Live cells were stained with calcein-AM (green), and dead cells were stained with propidium iodide (red.) (scale bar: 100 µm.) (D) In vivo fluorescence images of BxPC3 tumor-bearing, mice after intravenous injection of Cy5.5-labeled AuNCs/Dox, M@AuNCs/Dox and Col-M@AuNCs/Dox. (E) Temperature curves under NIR irradiation. (F) Tumor growth curves during different treatments (n=6) in BxPC3 tumor-bearing mice. Adapted from Yang XY, Zhang JG, Zhou QM et al. Extracellular matrix modulating enzyme functionalized biomimetic Au nanoplatform-mediated enhanced tumor penetration and synergistic antitumor therapy for pancreatic cancer. J Nanobiotechnology. 2022;20(1):524. Creative Commons. http://creativecommons.org/licenses/by/4.0/.

Figure 6

Schematic diagram and advantageous study of virus-mimicking cell membrane-coated nanoparticles in cytosolic delivery of mRNA. (A) Illustration of genetically engineered cell membrane-coated nanoparticles for the cytosolic delivery of mRNA. (B) Endosomal escape was observed through fluorescent visualization of B16-WT cells following incubation with WT-DiO-NP and HA-DiO-NP for 1, 4, 8, and 24 hours. Nuclei (blue), endosomes (red), nanoparticles (green); scale bar=20 mm. (C) mRNA transfection was conducted via bioluminescence monitoring over time in the serum of mice intravenously administered with WT-mRNA-NP and HA-mRNA-NP loaded with CLuc mRNA (n=5; mean SD). *p<0.05, **p<0.01 (compared to 0 h); Student’s t-test. (D) Visualization of bioluminescent signal from mice intranasally administered with WT-mRNA-NP and HA-mRNA-NP loaded with CLuc mRNA; high signal (H), low signal (L). Adapted from Park JH, Mohapatra A, Zhou J, et al. Virus-mimicking cell membrane-coated nanoparticles for cytosolic delivery of mRNA. Angew Chem Int Ed Engl. 2022;61(2):e202113671.© 2021 Wiley-VCH GmbH.

Figure 7

Schematic diagram and advantageous study of worm-Like biomimetic nanoerythrocyte carrying siRNA in melanoma gene therapy. Schematic illustration of (A) preparation and charge-reversible profile, (B) B16F10 tumor gene therapy, and (C) cell uptake and siRNA release profile from late endosome/lysosome escape of worm-like biomimetic nanoerythrocytes as targeting charge-reversible siRNA vectors. (D) Fluorescence images of two kinds of cells incubated with each gene vector (NP, RP, PP, and RBC-RP) for 4 h. (E) Biodistribution of cBSA, BSA sphere, RP, RBC-RP, and RGD-RBC-RP in B16F10 tumor-bearing BALB/c mice at 48 h after the injection. Results are expressed as mean ± SD (N = 4). *P < 0.05, **P < 0.01. Scale bars: 100 µm. (F) Relative tumor volume from tumor-bearing BALB/c mice with different treatment. Used with permission from Wang Y, Ji X, Ruan M, et al. Worm-like biomimetic nanoerythrocyte carrying siRNA for melanoma gene therapy. Small. 2018;14(47):e1803002. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.