Immune checkpoint inhibitors (ICIs) have obtained durable responses in many cancers, making it possible to foresee their potential in improving the health of cancer patients. However, immunotherapies are currently limited to a minority of patients and there is a need to develop a better understanding of the basic molecular mechanisms and functions of pivotal immune regulatory molecules. Immune checkpoint cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and regulatory T (Treg) cells play pivotal roles in hindering the anticancer immunity. Treg cells suppress antigen-presenting cells (APCs) by depleting immune stimulating cytokines, producing immunosuppressive cytokines and constitutively expressing CTLA-4. CTLA-4 molecules bind to CD80 and CD86 with a higher affinity than CD28 and act as competitive inhibitors of CD28 in APCs. The purpose of this review is to summarize state-of-the-art understanding of the molecular mechanisms underlining CTLA-4 immune regulation and the correlation of the ICI response with CTLA-4 expression in Treg cells from preclinical and clinical studies for possibly improving CTLA-4-based immunotherapies, while highlighting the knowledge gap.

CTLA-4 in Regulatory T Cells for Cancer Immunotherapy

Cell membrane-derived vesicles for delivery of therapeutic agents

Nanoparticle-based drug delivery systems have been synthesized from a wide array of materials. The therapeutic success of these platforms hinges upon their ability to favorably interact with the biological environment (both systemically and locally) and recognize the diseased target tissue. The immune system, composed of a highly coordinated organization of cells trained to recognize foreign bodies, represents a key mediator of these interactions. Although components of this system may act as a barrier to nanoparticle (NP) delivery, the immune system can also be exploited to target and trigger signaling cues that facilitate the therapeutic response stemming from systemic administration of NPs. The nano-bio interface represents the key facilitator of this communication exchange, where the surface properties of NPs govern their in vivo fate. Cell membrane-based biomimetic nanoparticles have emerged as one approach to achieve targeted drug delivery by actively engaging and communicating with the biological milieu. In this review, we will highlight the relationship between these biomimetic nanoparticles and the immune system, emphasizing the role of tuning the nano-bio interface in the immunomodulation of diseases. We will also discuss the therapeutic applications of this approach with biomimetic nanoparticles, focusing on specific diseases ranging from cancer to infectious diseases. Lastly, we will provide a critical evaluation on the current state of this field of cell membrane-based biomimetic nanoparticles and its future directions in immune-based therapy.

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Cell Membrane-Based Biomimetic Nanoparticles and the Immune System: Immunomodulatory Interactions to Therapeutic Applications.

Over the past decade, numerous studies have attempted to enhance the effectiveness of radiotherapy (external beam radiotherapy and internal radioisotope therapy) for cancer treatment. However, the low radiation absorption coefficient and radiation resistance of tumors remain major critical challenges for radiotherapy in the clinic. With the development of nanomedicine, nanomaterials in combination with radiotherapy offer the possibility to improve the efficiency of radiotherapy in tumors. Nanomaterials act not only as radiosensitizers to enhance radiation energy, but also as nanocarriers to deliver therapeutic units in combating radiation resistance. In this review, we discuss opportunities for a synergistic cancer therapy by combining radiotherapy based on nanomaterials designed for chemotherapy, photodynamic therapy, photothermal therapy, gas therapy, genetic therapy, and immunotherapy. We highlight how nanomaterials can be utilized to amplify antitumor radiation responses and describe cooperative enhancement interactions among these synergistic therapies. Moreover, the potential challenges and future prospects of radio-based nanomedicine to maximize their synergistic efficiency for cancer treatment are identified.

Nanomaterials for radiotherapeutics-based multimodal synergistic cancer therapy

The delicate compositions, structures, and functions of natural cell membranes provide ideal prototypes for the development of functional biomedical polymers. First, the cell membranes, e.g., the red blood cell membrane, can be directly utilized to coat the functional polymeric materials, achieving an excellent biocompatibility and long-term circulation in blood. Second, the lipids (particularly the phospholipids) and glycosylated molecules on the cell membranes help the design of anti-fouling and biocompatible biomaterials, which may also have high affinities to some specific molecules after a secondary modification. An interesting choline phosphate with the reverse order of phosphate choline in the cell membrane will be specifically discussed here. Third, the transmembrane/peripheral proteins and the channel structure of the cell membrane can also be used as prototypes of biomaterials with various functions, such as the recognition, separation, immobilization, and capture of biomolecules. This review describes such cell membrane bioinspired functional polymers for a variety of biomedical applications including drug/gene delivery, tissue engineering, implant materials, and molecular recognition and diagnosis. The structure–function relationships of these polymeric materials are discussed in detail. Finally, the challenges associated with these cell membrane bioinspired polymeric biomaterials are summarized.

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Bioinspired by cell membranes: functional polymeric materials for biomedical applications

Cancer remains a daunting and cureless disease, which is responsible for one-sixth of human deaths worldwide. These mortality rates have been expected to rise in the future due to the side effects of conventional treatments (chemotherapy, radiotherapy, and surgery), which can be addressed by applying nanomedicine. In order to escape from biological barriers, such nanomedicine should be mimicked and designed to be stealthy while navigating in the bloodstream. To achieve this, scientists take advantage of erythrocytes (red blood cells; RBCs) as drug carriers and develop RBC membrane (RBCm) coating nanotechnology. Thanks to the significant advances in nanoengineering, various facile surface functionalization methods can be applied to arm RBCm with not only targeting moieties, but also imaging agents, therapeutic agents, and nanoparticles, which are useful for theranostic nanomedicine. This review focuses on refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

Advances in refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

Atherosclerosis (AS), a typical chronic inflammatory vascular disease, is the main pathological basis of ischemic cardio/cerebrovascular disease (CVD). Long-term administration was characterized with low efficacy and serious side effects, while the macrophages with attractive intrinsic homing target have great potential in the efficient and safe management of AS. In this review, we focused on the systematical summary of the macrophage-based therapies in AS management, including macrophage autophagy, polarization, targeted delivery, microenvironment-triggered drug release, and macrophage- or macrophage membrane-based drug carrier. In conclusion, macrophage-based therapies have great promise to effectively manage AS in future research and clinic translation.

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Macrophage-Based Therapies for Atherosclerosis Management.

Obesity is associated with significant microvascular complications including renal injuries and may induce end-stage renal disease. Emerging studies have demonstrated microRNAs (miRNAs) are potential mediators in the pathophysiological process of nephropathy. The present study aimed to investigate the role of miR-802 in obesity-related nephropathy and potential molecular mechanisms. Through utilizing obese mouse model and human subjects, we explored the therapeutic benefits and clinical application of miR-802 in protecting against nephropathy. Renal miR-802 level was positively correlated with functional parameters, including blood urea nitrogen and creatinine in obese mice. Specific silencing of renal miR-802 improved high fat diet (HFD)-induced renal dysfunction, structural disorders and fibrosis. The up-regulated inflammatory response and infiltrated macrophages were also significantly decreased in miR-802 inhibitor-treated obese mice. Mechanistically, miR-802 directly bond to 3'-UTR of NF-κB-repressing factor (NRF) and suppressed its expression. In clinical study, the circulating miR-802 level was significantly increased in obese subjects, and positively correlated with plasma creatinine level but negatively correlated with creatinine clearance. Taken together, our findings provided evidence that miR-802/NRF signalling was an important pathway in mediating obesity-related nephropathy. It is a possible useful clinical approach of treating miR-802 inhibitor to combat nephropathy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.14193

MiR‐802 causes nephropathy by suppressing NF‐κB‐repressing factor in obese mice and human

Bacterial ghosts (BGs) are empty bacterial envelopes of Gram-negative bacteria produced by controlled expressions of cloned gene E, forming a lysis tunnel structure within the envelope of the living bacteria. Globally, BGs have been used as vaccine delivery systems and vaccine adjuvants. There is an increasing interest in the development of novel delivery systems that are based on BGs for biomedical applications. Due to intact reservation of bacterial cell membranes, BGs have an inherent immunogenicity, which enables targeted drug delivery and controlled release. As carrier vehicles, BGs protect drugs from interference by external factors. In recent years, there has been an increasing interest in BG-based delivery systems against tumors, inflammation, and infection, among others. Herein, we reviewed the preparation methods for BGs, interactions between BGs and the host, and further highlighted research progress in BG development.

Bacterial Ghosts-Based Vaccine and Drug Delivery Systems.

Food safety is related to the national economy and people’s livelihood. Fumonisins are widely found in animal feed, feed raw materials, and human food. This can not only cause economic losses in animal husbandry but can also have carcinogenicity or teratogenicity and can be left in animal meat, eggs, and milk which may enter the human body and pose a serious threat to human health. Although there are many strategies to prevent fumonisins from entering the food chain, the traditional physical and chemical methods of mycotoxin removal have some disadvantages, such as an unstable effect, large nutrient loss, impact on the palatability of feed, and difficulty in mass production. As a safe, efficient, and environmentally friendly detoxification technology, biological detoxification attracts more and more attention from researchers and is gradually becoming an accepted technique. This work summarizes the toxic mechanism of fumonisins and highlights the advances of fumonisins in the detoxification of biological antioxidants, antagonistic microorganisms, and degradation mechanisms. Finally, the future challenges and focus of the biological control and degradation of fumonisins are discussed.

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Libo Jin

Papers

Advances in refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

Macrophage-Based Therapies for Atherosclerosis Management.

MiR‐802 causes nephropathy by suppressing NF‐κB‐repressing factor in obese mice and human

Bacterial Ghosts-Based Vaccine and Drug Delivery Systems.

Toxic Mechanism and Biological Detoxification of Fumonisins