Golden Pen Award | The Current Status of Application of Biomembrane Nanocarrier Drug Delivery Systems in Tumor Immunotherapy

In recent years, the excellent biocompatibility, modifiability, and low immunogenicity of biomembrane nanosystems have significantly advanced the development of tumor immunotherapy. As a vital component of cells, biomembranes exhibit a bilayer structure primarily composed of lipids, proteins, and a small amount of carbohydrates, fulfilling critical roles in intercellular material exchange and information transmission. The surface of biomembranes retains the essential molecular structures and physicochemical properties of living cell surfaces, enabling them to evade clearance by the body. Consequently, encapsulating and assembling biomembranes with drugs into biomimetic drug-loaded nanoparticles not only enhances the biocompatibility of the nanoparticles but also significantly reduces the likelihood of their recognition and elimination by the reticuloendothelial system or mononuclear phagocytes in the human immune system after entering the bloodstream. Additionally, this approach can effectively inhibit the formation of protein coronas on the surface of nanoparticles. Natural biomembrane nanocarriers possess the following characteristics: (1) Retention of the basic physicochemical properties and biological activity of the cell membrane surface, ensuring good biocompatibility, safety, and biodegradability; (2) Low immunogenicity; (3) Ability to evade blood clearance, enabling long-lasting circulation and sustained drug release; (4) Surface amenable to genetic engineering modifications, facilitating the display of targeting peptides, functional proteins, and antibodies; (5) Cost-effectiveness, allowing for production through cellular engineering.

Tumor immunotherapy involves activating the body's own anti-tumor immune response to attack tumor cells, effectively inhibiting tumor initiation, progression, and recurrence. Through long-term research and exploration, the current primary methods of tumor immunotherapy include immunostimulatory cytokines, monoclonal antibodies, immune checkpoint inhibitors, tumor vaccines, and modulation of the immune microenvironment. Studies have shown that nanoparticles disguised with biomembranes can better adapt to the complex physiological environment of the body. By leveraging the unique surface physicochemical properties of biomembranes, the delivery efficiency of cytokines, monoclonal antibodies, and immune checkpoint inhibitors can be enhanced, thereby effectively regulating immune cells such as antigen-presenting cells (APCs), dendritic cells, or T cells.

1. Application of Biomembrane Nanosystems in Immunostimulatory Cytokines

Interleukin (IL) is a class of cytokines produced by various cells and acts on multiple cells, playing a crucial role in information transmission, mediating immune cell proliferation and activation, as well as various inflammatory responses. Recombinant interleukin-2 (rIL-2), as an important immunostimulatory cytokine, has played a significant role in regulating apoptosis. It was approved by the U.S. Food and Drug Administration (FDA) in 1992 for the treatment of metastatic renal cell carcinoma and in 1998 for the treatment of metastatic melanoma.

When rIL-2 was adsorbed into nanovesicles loaded with doxorubicin (NV-DOXIL-2) and intravenously injected into melanoma mice, it was found that NV-DOXIL-2 accumulated at the tumor site, significantly inhibiting tumor growth, reducing the loss of rIL-2 in the bloodstream, and controlling its sustained release at the tumor site. This promoted the maturation of dendritic cells and the infiltration and activation of CD8+ T lymphocytes and natural killer cells. Tumor microenvironment-responsive nanodrug carriers have been widely studied due to their excellent controlled release effects. By leveraging the specific adsorption of immune stimulatory factors onto the cell membrane surface, the design and functionality of biomembrane-based nanodrug particles can be diversified. For example, using red blood cell membranes to adsorb IL-2 while encapsulating pH-responsive hydrogels loaded with paclitaxel, the resulting biomembrane nanoparticles exhibit both tumor microenvironment pH-responsive properties to control drug release and the ability to modulate the tumor immune microenvironment, stimulating the body's immune response and thereby significantly enhancing the effectiveness of tumor chemotherapy.

2.Application of Biomembrane Nanosystems in Monoclonal Antibodies and Immune Checkpoint Inhibitors

In tumor immunotherapy, CTLA-4 monoclonal antibodies and PD-1/PD-L1 monoclonal antibodies are representative immune checkpoint inhibitors. In 2011, clinical trials confirmed that the CTLA-4 antibody Ipilimumab could significantly improve the survival rate of cancer patients, leading to its approval by the U.S. FDA for the treatment of metastatic melanoma. In 2014, two PD-1 checkpoint inhibitors, Nivolumab and Pembrolizumab, were approved for the treatment of melanoma. Between 2015 and 2016, the U.S. FDA successively approved Nivolumab, Atezolizumab, and Pembrolizumab as second-line treatments for melanoma and non-small cell lung cancer. The series of groundbreaking research advancements in immune checkpoint inhibitors were awarded the Nobel Prize in Physiology or Medicine in 2018. However, due to the lack of effective in vivo delivery strategies, free antibodies have a short circulation time in the blood and are easily cleared by the bloodstream, reducing their biological activity and preventing effective accumulation at the target site, thereby diminishing their therapeutic efficacy.

Utilizing genetic engineering techniques, monoclonal antibodies can be directly modified onto the surface of biomembranes, serving as tumor-targeting molecules. This approach enables the fabrication of biomembrane-based nanodrug delivery systems with tumor-specific targeting capabilities. Researchers have expressed full-length antibodies against liver cancer-specific membrane protein GPC3 and ovarian cancer-specific membrane protein Claudin4 on the cell membrane surface, yielding multifunctional nanovesicles with targeting abilities. When loaded with contrast agents, these nanovesicles can achieve multimodal imaging of live tumor sites. Furthermore, by loading chemotherapeutic drugs, they can facilitate targeted drug delivery to tumors and initiate antibody-dependent cellular cytotoxicity (ADCC) at the tumor site. This research, based on cell membrane nanocarriers, utilizes monoclonal antibodies to target tumor sites, guiding the delivery of tumor drugs and achieving a combination of chemotherapy and immunotherapy strategies.

In another study, PD-L1 was genetically engineered to be expressed on the membrane of 293T cells, and vesicles extracted from these cells were loaded with 1-methyl-tryptophan (1-MT), an immune agonist, to form membrane-encapsulated nanoparticles. On one hand, the binding of PD-1 to PD-L1 on the surface of 293T cells restores the immune activity of T cells. On the other hand, the binding of 1-MT to indoleamine 2,3-dioxygenase (IDO), an immunosuppressive molecule expressed on the surface of dendritic cells, breaks the immune silence of dendritic cells, thereby initiating an anti-tumor immune response. Expressing PD-L1 on the cell membrane is an effective strategy to preserve its biological activity.

3.Application of Biomembrane Nanosystems in Cancer Immunotherapy

Cancer immunotherapy involves harnessing tumor-associated antigens in conjunction with other immune-stimulatory factors to induce the body's specific cellular and humoral immune responses, thereby inhibiting tumor cell growth, metastasis, and recurrence. In April 2010, the U.S. FDA approved the first cancer treatment vaccine, Sipuleucel-T (Provenge), for the treatment of advanced prostate cancer, marking a significant advancement and spurring research and development in the field of cancer immunotherapy.

For a long time, the targeting, efficacy, and safety of tumor antigen presentation have posed significant constraints on the development of cancer immunotherapy. By utilizing the membrane of mouse melanoma cells to encapsulate oligonucleotide adjuvant molecules to form nanoparticles, the composition and physicochemical properties of the tumor cell surface are relatively intactly preserved on the surface of these nanoparticles. This camouflage strategy can increase the blood circulation time of the nano-immunotherapy agents and target lymph nodes, effectively inducing the maturation of antigen-presenting cells, stimulating T-cell proliferation, and eliciting immune responses. These nanovesicles derived from tumor cell membranes, which carry tumor-specific antigens on their surface, overcome the issues of high mutation rates and diverse antigen expression patterns observed in tumor antigens.

Furthermore, hybrid cell membranes constructed from tumor cells and dendritic cells can be used to create nano-immunotherapy agents. The surface of these agents possesses a variety of specific molecules from both tumor cells and immune cells, enabling them to mimic the function of antigen-presenting cells and directly activate T-cell-mediated anti-tumor immune responses.

4.Modulation of the Immune Microenvironment by Biomembrane Nanosystems

Research has demonstrated that regulating the inflammatory response within the tumor microenvironment can effectively inhibit tumor invasion and infiltration, thereby enhancing the efficacy of cancer immunotherapy and suppressing tumor metastasis and recurrence. Studies have confirmed that neutrophils can enhance the metastatic capability of circulating tumor cells (CTCs) by releasing abundant cytokines. When the release of these cytokines is blocked, the cancer-promoting effect of neutrophils is also inhibited. Inspired by this mechanism, a nanoscale drug delivery system (NM-NPs) that mimics neutrophils has been developed. The surface of polylactic acid nanoparticles is coated with neutrophil membranes, while their cores are loaded with the second-generation proteasome inhibitor, Carfilzomib. Compared to uncoated nanoparticles, NM-NPs exhibit stronger cellular association and a significantly higher ability to target CTCs in an early metastasis model of 4T1 tumor cells. NM-NPs effectively promote the apoptosis of CTCs in the bloodstream, prevent the formation of early nodules, and induce tumor cell apoptosis and inhibit metastasis in the 4T1 cell metastasis model.

The application of biomembrane nanodelivery systems in cancer immunotherapy can effectively protect the biological activity of immune-related molecules such as tumor antigens, enabling their long-term circulation in the bloodstream and targeted delivery to tumor sites. Additionally, through targeted modifications and improvements, this approach can address many difficulties and challenges faced by current cancer immunotherapy strategies, thereby holding immense potential for clinical translation. While the integration of biomembrane nanosystems into cancer immunotherapy presents vast translational opportunities, it also comes with numerous challenges, including interactions between the biomembrane and nanomedicine, the potential loss of native activity during extraction and preparation processes, and difficulties in industrial-scale manufacturing. Nevertheless, with continued in-depth exploration and research, it is believed that tumor immunotherapy based on biomembrane nanosystems will achieve greater breakthroughs and broader applications, ultimately advancing human efforts in the fight against cancer.

References:

[1] Huang Jie, Zhang Zhen, He Xiaofang, Yang Mi, Hu Jing, Li Li, Liu Baorui, Qian Xiaoping. Research Progress on Tumor-Targeting Biomembrane Nanodrug Delivery Systems. Journal of Southeast University (Medical Science Edition), 2017, 36(05): 864-868.

[2] Tian Ye, Zhang Yang, Wang Xiaoyong, Liu Gang. Advances in the Application of Biomembrane Nanodrug Delivery Systems in Tumor Immunotherapy. China Pharmacy, 2020, 31(05): 636-640.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.