Artificial cells are constructed to imitate natural cells and allow researchers to explore biological process and the origin of life. The construction methods for artificial cells, through both top-down or bottom-up approaches, have achieved great progress over the past decades. Here we present a comprehensive overview on the development of artificial cells and their properties and applications. Artificial cells are derived from lipids, polymers, lipid/polymer hybrids, natural cell membranes, colloidosome, metal-organic frameworks and coacervates. They can be endowed with various functions through the incorporation of proteins and genes on the cell surface or encapsulated inside of the cells. These modulations determine the properties of artificial cells, including producing energy, cell growth, morphology change, division, transmembrane transport, environmental response, motility and chemotaxis. Multiple applications of these artificial cells are discussed here with a focus on therapeutic applications. Artificial cells are used as carriers for materials and information exchange and have been shown to function as targeted delivery systems of personalized drugs. Additionally, artificial cells can function to substitute for cells with impaired function. Enzyme therapy and immunotherapy using artificial cells have been an intense focus of research. Finally, prospects of future development of cell-mimic properties and broader applications are highlighted.

Artificial Cells: Past, Present and Future.

Cerium-based nanoparticles (CeNPs), particularly cerium oxide (CeO2), have been studied extensively for their antioxidant and prooxidant properties. However, their complete redox and enzyme-mimetic mechanisms of therapeutic action at the molecular level remain elusive, constraining their potential for clinical translation. Although the therapeutic effects of both antioxidant and prooxidant mechanisms generally are attributed to Ce3+ ↔ Ce4+ redox switching mediation, some studies have hinted at the involvement of unknown pathways in therapeutic effects. While redox switching is recognised increasingly as playing a key role in ROS-dependent cancer therapy, ROS-independent cytotoxicity mechanisms, such as Ce4+ dissolution and autophagy, also are emerging as being of importance. Although ROS-mediated prooxidant therapies are the most intensively studied, particularly in the context of cancer, the antioxidant activity deriving from the redox switching, particularly during radiation therapy, also plays an important role in the protection of normal cells during radiation therapy, hence reducing adverse effects. Since cancer cell proliferation results in aberrant behaviour of the tumour microenvironment (TME), then CeNP-based therapies are being used to address a multiplicity of known and unknown factors that aim to normalise the TME and thus prevent this aberrant behaviour. Although it is perceived that the pH plays a key role in the therapeutic performance of cerium-based nanoparticles, this is not conclusive because the relative importances of other factors, particularly Ce dissolution, Ce3+/Ce4+ ratio, cellular H2O2 level, and the role of anions, remain poorly understood. Consequently, the present work explores these multiple chemistry-driven mechanisms, which are both ROS-dependent and ROS-independent, in cancer therapy.

Anticancer therapeutic effect of cerium-based nanoparticles: known and unknown molecular mechanisms.

Enzymes featuring high catalytic efficiency and selectivity have been widely used as the sensing element in analytical chemistry. However, the structural fragility and poor machinability of an enzyme significantly limit its practicability in biosensors. Herein, we develop a robust and sensitive hybrid biosensor by means of co-encapsulating enzymes into a defective metal-organic framework (MOF), followed by a double-crosslinked alginate gelatinization. The defective MOF encapsulation can enhance the stability of enzymes, yet well preserve their biocatalytic function, while the alginate gelatinization allows the MOF biohybrid high stretchability and mechanical strength, which facilitates the integration of a bead-, fiber-, and sheet-like portable biosensor. In this work, the enzymes consisting of glucose oxidase and peroxidase are co-encapsulated into this MOF hydrogel, and it can efficiently convert glucose into a blue-violet product through the biocatalytic cascade of encapsulated enzymes, enabling the colorimetric biosensing of glucose on a miniaturized MOF hydrogel when coupling with a smartphone. Interestingly, this MOF biohybrid hydrogel outputs a stronger sensing signal than the free biohybrid powders, attributed to the catalytic product-accumulated effect of the highly hydrophilic microenvironment of the hydrogel. As a result, this portable biosensor can sensitively and selectively sense glucose with a linear range from 0.05 to 4 mM. Importantly, both the hydrophilic hydrogel and MOF "armor" endow enzymes with high durability, and its sensing activity was well-maintained even after placing the biosensor at room temperature for 30 d. We believe that this MOF biohybrid hydrogel has huge potential for the engineering of next-generation portable biosensors.

Enzymes-Encapsulated Defective Metal-Organic Framework Hydrogel Coupling with a Smartphone for a Portable Glucose Biosensor.

Melanoma is the most aggressive type of skin cancer, the incidence and mortality of which are increasing worldwide. Its extensive degree of heterogeneity has limited its response to existing therapies. For many years the therapeutic strategies were limited to surgery, radiotherapy, and chemotherapy. Fortunately, advances in knowledge have allowed the development of new therapeutic strategies. Despite the undoubted progress, alternative therapies are still under research. In this context, nanotechnology is also positioned as a strong and promising tool to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve photothermal and photodynamic therapies outcomes. This review describes the latest advances in nanotechnology field in the treatment of melanoma from 2011 to 2022. The challenges in the translation of nanotechnology-based therapies to clinical applications are also discussed. To sum up, great progress has been made in the field of nanotechnology-based therapies, and our understanding in this field has greatly improved. Although few therapies based on nanoparticulate systems have advanced to clinical trials, it is expected that a large number will come into clinical use in the near future. With its high sensitivity, specificity, and multiplexed measurement capacity, it provides great opportunities to improve melanoma treatment, which will ultimately lead to enhanced patient survival rates.

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How to Treat Melanoma? The Current Status of Innovative Nanotechnological Strategies and the Role of Minimally Invasive Approaches like PTT and PDT

Nanotechnology is one of the scientific advances in technology. Nanoparticles (NPs) are small materials ranging from 1 to 100 nm. When the shape of the supplied nanoparticles changes, the physiological response of the cells can be very different. Several characteristics of NPs such as the composition, surface chemistry, surface charge, and shape are also important parameters affecting the toxicity of nanomaterials. This review covered specific topics that address the effects of NPs on nanomedicine. Furthermore, mechanisms of different types of nanomaterial-induced cytotoxicities were described. The distributions of different NPs in organs and their adverse effects were also emphasized. This review provides insight into the scientific community interested in nano(bio)technology, nanomedicine, and nanotoxicology. The content may also be of interest to a broad range of scientists.

https://www.mdpi.com/1422-0067/23/14/7597/pdf?version=1657530974

Toxicologic Concerns with Current Medical Nanoparticles

Angiogenesis plays a key role in cancer progression, including transition to the metastatic phase via reactive oxygen species (ROS)-dependent pathways, among others. Antivascular endothelial growth factor (VEGF) antibodies have been trialed as an anti-angiogenic therapy for cancer but are associated with high cost, limited efficacy, and side effects. Cerium oxide nanoparticles (nanoceria) are promising nanomaterials for biomedical applications due to their ability to modulate intracellular ROS. Nanoceria can be produced by a range of synthesis methods, with chemical precipitation as the most widely explored. It has been reported that chemical precipitation can fine-tune primary particle size where a limited number of synthesis parameters were varied. Here, we explore the effect of temperature, precipitating agent concentration and rate of addition, stirring rate, and surfactant concentration on nanoceria primary particle size using a fractional factorial experimental design approach. We establish a robust synthesis method for faceted nanoceria with primary particle diameters of 5-6 nm. The nanoceria are not cytotoxic to a human melanoma cell line (Mel1007) at doses up to 400 μg/mL and are dose-dependently internalized by the cells. The intracellular ROS level for some cells that internalized the nanoceria is reduced, which correlates with a dose-dependent reduction in angiogenic gene expression including VEGF. These findings contribute to our knowledge of the anti-angiogenic effects of nanoceria and help to develop our understanding of potentially new anti-angiogenic agents for combination cancer therapies.

ROS-Mediated Anti-Angiogenic Activity of Cerium Oxide Nanoparticles in Melanoma Cells.

Advances in artificial/synthetic cells have drawn a new era of nanobiotechnology, which have shown broad prospects in biomedical applications. The rational nanoengineering of synthetic cells that can closely substitute the systematic biological functions of cells is a next grand challenge. Here, a genetically encoded synthetic beta cell, which can sense hyperglycemic conditions to initiate programmed biosynthesis and secretion of insulin is reported. By encapsulating different metal–organic framework‐based artificial organelles with distinctive bifunctionalities, the synthetic cell can undergo programmed, sequential subcellular events, including glucose sensing, initiation of insulin gene transcription and translation, and finally excretion of functional insulin, under hyperglycemic conditions. Glucose uptake assay suggests that the insulin produced by the synthetic cells can successfully promote glucose uptake into mammalian cells. The construction of a higher‐order cell cluster by ligand‐mediated super‐assembly of the synthetic cells is further demonstrated. Such a robust and smart synthetic system that closely mimics the cellular activities of beta cells in response to glucose levels is promising for improving clinical outcomes in diabetes treatment.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/adfm.202111271

Genetically Encoded Synthetic Beta Cells for Insulin Biosynthesis and Release under Hyperglycemic Conditions

The role of the cell surface glycocalyx in drug delivery to and through the endothelium.

Abstract Inadequate angiogenesis is a hallmark of conditions including cardiovascular diseases, stroke and chronic diabetic wounds, which exhibit tissue ischaemia ensuring that therapeutic strategies to promote angiogenesis are of great interest. However, many angiogenic treatments involve the delivery of growth factors which have limited clinical success due to poor stability, high manufacturing cost and poor efficacy. Cerium oxide nanoparticles (nanoceria) can either promote or inhibit angiogenesis depending on their surface corona chemistry. Here, nanoceria were functionalized with an intentional heparin corona, a polysaccharide which binds and signals growth factors, of different chain lengths and surface grafting density to establish their effect on angiogenesis. These nanoparticles promoted angiogenesis in vivo with the surface grafting density positively correlated with angiogenesis over the widest concentration range; however, chain length did not play a role. The heparin–nanoceria supported fibroblast growth factor 2 (FGF2) signalling in vitro and promoted FGF2-mediated angiogenesis in vivo. The nanoparticles were internalized by endothelial cells in vitro where they trafficked to the lysosomes and reduced cell viability suggesting that the angiogenic activity of heparin–nanoceria is mediated in the extracellular environment. Together, this study adds to our knowledge of the angiogenic effects of heparin–nanoceria towards finding new angiogenic treatments.

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Tuning the intentional corona of cerium oxide nanoparticles to promote angiogenesis via fibroblast growth factor 2 signalling

Strategies to promote rapid formation of functional endothelium are required to maintain blood fluidity and regulate smooth muscle cell proliferation in synthetic vascular conduits. In this work, we explored the biofunctionalization of silk biomaterials with recombinantly expressed domain V of human perlecan (rDV) to promote endothelial cell interactions and the formation of functional endothelium. Perlecan is essential in vascular development and homeostasis and rDV has been shown to uniquely support endothelial cell, while inhibiting smooth muscle cell and platelet interactions, both key contributors of vascular graft failure. rDV was covalently immobilized on silk using plasma immersion ion implantation (PIII), a simple one-step surface treatment process which enables strong immobilization in the absence of chemical cross-linkers. rDV immobilization on surface-modified silk was assessed for amount, orientation, and bio-functionality in terms of endothelial cell interactions and functional endothelial layer formation. rDV immobilized on PIII-treated silk (rDV-PIII-silk) supported rapid endothelial cell adhesion, spreading, and proliferation to form functional endothelium, as evidenced by the expression of vinculin and VE-cadherin markers. Taken together, the results provide evidence for the potential of rDV-PIII-silk as a biomimetic vascular graft material.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jbm.a.37525

Recombinant perlecan domain V covalently immobilized on silk biomaterials via plasma immersion ion implantation supports the formation of functional endothelium.

Lu Fu

Papers

ROS-Mediated Anti-Angiogenic Activity of Cerium Oxide Nanoparticles in Melanoma Cells.

Genetically Encoded Synthetic Beta Cells for Insulin Biosynthesis and Release under Hyperglycemic Conditions

The role of the cell surface glycocalyx in drug delivery to and through the endothelium.

Tuning the intentional corona of cerium oxide nanoparticles to promote angiogenesis via fibroblast growth factor 2 signalling

Recombinant perlecan domain V covalently immobilized on silk biomaterials via plasma immersion ion implantation supports the formation of functional endothelium.