In recent years, with the development of biomedicine, the cell membrane-mediated nano-drug delivery system based on biomimetic technology has become a promising delivery strategy for targeted tumor therapy using nanotechnology. This is due to its organic integration of the low immunogenicity of natural biomembranes, tumor targeting ability, as well as the controllability and multifunctionality of intelligent nano-carrier design. Common biomimetic nano-formulations derived from biological membranes include tumor cell membranes, red blood cell membranes, platelet membranes, leukocyte membranes, stem cell membranes, extracellular vesicles (exosomes, microvesicles, and apoptotic bodies), endoplasmic reticulum membranes, and composite biomembranes.

Related Reading: "Research Progress in Biomimetic Nanomaterials for Biomembrane Applications (Part I)"

5.Stem Cell Membrane-Inspired Drug Delivery System

Stem cells are a type of cells with unlimited or immortal self-renewal abilities, capable of producing at least one type of highly differentiated offspring cells. They mainly include embryonic stem cells, mesenchymal stem cells, hematopoietic stem cells, etc. Among them, mesenchymal stem cells are easy to obtain in vitro and can be cultured in large quantities. Genomic studies have proven that there are targets on their surface that can recognize tumor cells. Therefore, stem cells are able to target tumor cells and track infiltrating tumor cells. The stem cell membrane-inspired drug delivery system not only retains the complex biological functions of stem cells but also ensures the circulation time of nanoparticles in the body.

According to research reports, the use of traditional co-extrusion methods to coat mesenchymal stem cell membranes onto silica nanoparticles for photodynamic therapy of tumors has found that the new nano-platform retains the tumor targeting properties of mesenchymal stem cells, significantly enhancing tumor suppression effects, providing new ideas for photodynamic and photothermal therapies for tumors. Some scholars have designed biodegradable manganese dioxide (HMnO2) nanoparticles (NP) coated with human umbilical cord mesenchymal stem cell (hUC-MSC) membranes. Pharmacodynamic experiments have shown that intravenous injection of this biomimetic drug can significantly inhibit tumor growth, recurrence, and metastasis, and effectively promote the maturation of dendritic cells, recruiting effector T cells to the tumor. Using human umbilical cord mesenchymal stem cell membranes as a drug carrier for nanoparticles to encapsulate isotretinoin, stem cell membrane-isotretinoin nanoparticles were prepared. In vitro skin permeation experiments showed a significant improvement in the skin permeation ability of isotretinoin. In vivo experiments showed that stem cell membrane-isotretinoin nanoparticles can effectively reduce the skin irritation caused by isotretinoin and significantly improve follicular comedones and acne in a rabbit ear acne model. Additionally, the fusion membrane constructed by fusing liposome membranes with stem cell membranes serves as a novel platform technology, demonstrating advantages such as controlled drug release, good stability, long-term circulation in the body, and targeted delivery.

6.Extracellular Vesicle-Inspired Drug Delivery System

Extracellular vesicles can be classified into exosomes, microvesicles, and apoptotic bodies based on their size and origin. Exosomes are extracellular vesicles secreted by cells in a form of exocytosis under physiological or pathological conditions, with a diameter of approximately 40 to 100 nm. They are composed of a lipid bilayer. Various cells can secrete exosomes under normal and pathological conditions. They mainly originate from multivesicular bodies formed by the invagination of lysosomal particles within cells, which selectively receive and load nucleic acids, proteins, and lipids from the cell cytoplasm. These loaded exosomes are then released into the extracellular matrix after the fusion of the outer membrane of the multivesicular bodies with the cell membrane. All types of cells cultured in vitro can secrete exosomes, and exosomes naturally exist in bodily fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes possess good biocompatibility and encapsulation properties. Besides encapsulating drugs for delivery, exosomes themselves also have great potential in tumor diagnosis and treatment.

Research has confirmed that ATDC5-derived exosomes loaded with the drug 5Z-7 can alleviate osteoarthritis phenotypes in both in vivo and in vitro experiments, reducing drug dosage and administration frequency. Microvesicles are large vesicles formed by the protrusion of the cell plasma membrane towards the extracellular space, which can be generated by body cells under physiological and pathological conditions. Small extracellular vesicles derived from mesenchymal stem cells were collected using ultracentrifugation to investigate their effects on retinal photodamage in mice and their possible mechanisms. Experiments have demonstrated that small extracellular vesicles derived from mesenchymal stem cells can alleviate retinal structural and functional damage caused by blue light. This protective effect may be achieved by inhibiting inflammatory responses. Apoptotic bodies are small, bubble-like structures formed by the shrinkage and invagination of the cell membrane, enclosing cytoplasm, DNA material, and cell organelles. The formation of apoptotic bodies can occur through budding or autophagy. Studies suggest that apoptotic bodies can be ingested by monocytes/macrophages in the body and targeted to tumors along with the homing behavior of circulating monocytes, infiltrating the central region of tumors. Therefore, apoptotic bodies loaded with the drug R848 nanoparticles modified with IR-820 can be prepared as functional drug-loaded apoptotic bodies (R848 NP/AB-IR). Experiments have shown that R848 NP/AB can activate dendritic cells (DCs) in vitro, polarize M2 macrophages into M1, and synergistically enhance the phagocytic effect of macrophages on tumor cells when combined with an aCD47 antibody.

7.Endoplasmic Reticulum Membrane-Inspired Drug Delivery System

The endoplasmic reticulum (ER) is a crucial organelle in eukaryotic cells, responsible for regulating calcium homeostasis, protein synthesis, processing, and transport. Leveraging the working principle of intracellular vesicle transport from the Golgi apparatus back to the ER, drug-loaded particles can traverse a non-degradative "endosome-Golgi apparatus-ER" pathway, effectively evading degradation and destruction via the "endosome-lysosome" pathway, thereby improving cellular uptake. Research reports have shown that using ER membranes extracted from tumor cells to modify cationic lipid nanocarriers can produce a biomimetic siRNA delivery vector. This biomimetic vector can effectively promote cellular uptake and significantly increase the effective release of siRNA in the cytoplasm, leading to improved siRNA gene silencing effects and anti-tumor effects. It has achieved a tumor inhibition rate of approximately 80% in nude mice with orthotopic MCF-7 breast tumors.

8.Composite Biomimetic Drug Delivery System

With the continuous development of membrane biomimetic technology, more and more research has focused on fusing membranes from two different sources to prepare hybrid membrane biomimetic nanoparticles, aiming to achieve an organic combination of different biological membrane functions. The criteria for selecting cell membranes mainly depend on the unique characteristics of different cells and the needs of disease treatment. Research reports have shown that nanoparticles coated with red blood cell-platelet hybrid membranes possess surface membrane protein markers from both cell types. The resulting dual-membrane-coated nanoparticles exhibit good long-circulating and distribution properties in mouse models. Compared to single-membrane red blood cell-coated nanoparticles and platelet-coated nanoparticles, the hybrid membrane-coated nanoparticles display cross-characteristics of both single-membrane coated nanoparticles. Some scholars have designed a composite biomimetic nano-drug delivery system combining tumor cell membranes and red blood cell membranes, which retains the targeting ability of tumor cells while carrying the function of red blood cells to produce and carry CO. This allows for selective accumulation of CO in tumors and in situ generation of CO under red light irradiation, which can be used for tumor chemotherapy and gas therapy.

Biomimetic drug delivery systems based on biomembrane-wrapped nanoscale natural particles can mimic the functions and biological processes of endogenous substances in the human body, accurately and targetedly delivering drugs to the target site, achieving the purpose of precision therapy with reduced adverse reactions, excellent treatment effects, and low immunogenicity. However, both the development time and production costs of biomimetic nanodrugs are inevitable issues for traditional research teams. Therefore, the research and application of biomimetic nanodrugs based on biomembranes are still in their infancy, and there are some challenges and issues in experimental production.

Firstly, the extraction and separation process of biomembranes is not yet mature. Most often, repeated freeze-thaw cycles combined with differential centrifugation are used to prepare cell membranes. While this method is simple and fast, allowing for large-scale preparation in a short time, it lacks specificity, resulting in unpredictable product yield. Additionally, it is difficult to remove other cell debris, reducing the repeatability of subsequent experiments.

Secondly, there are concerns regarding the safety of biomembranes. Although numerous studies have demonstrated the low immunogenicity of biomembrane-based biomimetic nanodrugs, verification experiments are still conducted in animals for a short period. For the human body, biomembrane-based biomimetic nanodrugs remain foreign substances, and it is unknown whether long-term use will lead to adverse reactions. Additionally, the potential introduction of heat sources, viruses, or other contaminants during the process of wrapping nanoparticles with biomembranes needs to be considered. On the other hand, whether tumor cell membranes retain carcinogenic factors is also a matter that requires further investigation.

Therefore, how to develop a time- and effort-saving method for preparing biomembranes with high purity while further confirming their safety remains an urgent problem to be addressed.

References

[1] Zhang Qiang, Luo Xi, Bao Yongrui, et al. Research Progress of Biomimetic Nano-preparations Based on Biomembranes [J/OL]. Journal of China Pharmaceutical University: 1-15 [retrieved on 2023-11-01].

[2] Huang Lingling, Wu Honghui, Xu Donghang, et al. Research Progress of Cell Membrane Biomimetic Nanotechnology in Tumor-Targeted Drug Delivery Systems [J]. Acta Pharmaceutica Sinica, 2022, 57(01): 85-97+276.

[3] Shi Wen, Hu Fangfang, Yin Tieying, Wang Yazhou. Research Progress in Tumor Treatment Using Cell Membrane Biomimetic Modified Nanoparticles [J]. Progress in Biochemistry and Biophysics, 2022, (Issue 3).

[4] Jia Hongxin, Zhang Yan. Research Progress of Cell Membrane Biomimetic Nano Drug Delivery System in Tumor Therapy [J]. China Science and Technology Periodicals Database (Medicine), 2021, (Issue 3).

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.