Cell-based therapy has expanded its influence in cancer immunotherapy, regenerative medicine, and tissue engineering. Due to their secretory functions, differentiation capabilities, specific homing effects through chemotaxis, distinctive therapeutic potentials, and ex vivo expandability, cells have become an attractive reagent for advanced therapeutic strategies. Therefore, the ability to modify cells and manipulate their functions according to intended therapeutic designs has been the central scientific interest in the field of biomedical research. Many innovative methods have been developed with genetic modification of cells being the most advanced cell surface engineering technique. Although genetic modification is a powerful tool, it has a limited applicability due to the permanent modifications made on cells. Alternatively, many endeavors have been made to develop surface engineering techniques that can circumvent the limitations of genetic modification. In this review, current methods of non-genetic cell surface modification, including chemical conjugations, polymeric encapsulation, hydrophobic insertion, enzymatic and metabolic addition, will be introduced. Moreover, cell surface engineering plausible for cardiac remodeling and the future prospective will be discussed at the end.

Metal nanoparticles are widely used for the delivery and targeting of pharmaceutical, therapeutic and diagnostic agents in cancer therapy in recent years. The multifunctional nanoparticles constructed currently are supposed to show superior effects on cancer cells. This study was conducted to observe the difference between the effect of a biologically important peptide, silver (AgNPs) and gold (AuNPs) nanoparticles and their conjugates on two different cancer cells. Peptide (Boc-L-DP-L-OMe) was acquired from different sources and subjected to conjugation with biosynthesized gold and silver nanoparticles under standard conditions. These conjugates were tested against the colon cancer (HT-29) and breast cancer (MDA MB-231) cell lines. The results clearly depicted the improved activity of nanoparticles in the form of conjugates. Fluorescent dye microscopy and DNA fragmentation assay substantiate the fact that the conjugated nanoparticles cause higher level of disintegration of DNA in cells that consecutively damages and causes apoptosis due to lethality.

The Lewis alpha (1-->3/4)-fucosyltransferase (Le-FucT) is known to fucosylate both Type I (beta Gal(1-->3) beta GlcNAc) and Type II (beta Gal(1-->4) beta GlcNAc) sequences even when these are sialylated at OH-3 or fucosylated at OH-2 of the terminal Gal residues. These acceptor sequences are ubiquitous on mammalian cell-surface glycoproteins and glycolipids. The Le-FucT enzyme is therefore a potential candidate as a universal reagent for the modification of cell surfaces. It is proposed that the Le-FucT represents a powerful new tool with the ability to label animal cell surfaces with preassembled oligosaccharide and possibly also other complex recognition markers.

To optimize live cell fluorescence imaging, the choice of fluorescent substrate is a critical factor. Although genetically encoded fluorescent proteins have been used widely, chemical fluorescent dyes are still useful when conjugated to proteins or ligands. However, little information is available for the suitability of different fluorescent dyes for live imaging. The authors here systematically analyzed the property of a number of commercial fluorescent dyes when conjugated with antigen-binding (Fab) fragments directed against specific histone modifications, in particular, phosphorylated H3S28 (H3S28ph) and acetylated H3K9 (H3K9ac). According to the authors‘ analysis, conjugation with green fluorescent dyes has the least effect on Fab affinity and is the best for live cell imaging, although these dyes are less photostable than red fluorescent dyes.

The authors engineer cell membranes with β-cyclodextrin and subsequently manipulate cell behaviours via photo-responsive host-guest recognition. With this methodology, they demonstrate reversible manipulation of cell assembly and disassembly. The method enables light-controllable reversible assembly of cell–cell adhesion, in contrast with previously reported irreversible effects, in which altered structure could not be reused. They also illustrate the utility of the method by designing a cell-based therapy. Peripheral blood mononuclear cells modified with aptamer are effectively redirected towards target cells, resulting in enhanced cell apoptosis.

Core fucosylation is one of the most important glycosylation events in the progression of liver cancer. For this study, the authors used an easily handled L-fucose analog, 2-fluoro-L-fucose (2FF), which interferes with the normal synthesis of GDP-fucose, and verified its potential roles in regulating core fucosylation and cell behavior in the HepG2 liver cancer cell line. The results clearly described the roles of 2FF and the importance of core fucosylation in liver cancer progression, suggesting 2FF shows promise for use in the treatment of hepatoma.

Revolutionary progress in stem cell research and the potential of stem cell‐based therapeutics promote the translation of cell therapy. However, the therapeutic efficacy of cell therapy is still very low, mainly because of the insufficient homing and survival of the injected cells at the target site. Cell surface engineering is one of the solutions to increase the therapeutic efficacy of cell therapy. Cell surface engineering can modulate the cellular behavior for enhancing targeted delivery, cellular functions, organized structure, and immune evasion by chemical or physical modification of the cell surface. This review summarizes the recent studies in cell surface engineering focused on cell therapy.

Cell-based therapy has expanded its influence in cancer immunotherapy, regenerative medicine, and tissue engineering. Due to their secretory functions, differentiation capabilities, specific homing effects through chemotaxis, distinctive therapeutic potentials, and ex vivo expandability, cells have become an attractive reagent for advanced therapeutic strategies. Therefore, the ability to modify cells and manipulate their functions according to intended therapeutic designs has been the central scientific interest in the field of biomedical research. Many innovative methods have been developed with genetic modification of cells being the most advanced cell surface engineering technique. Although genetic modification is a powerful tool, it has a limited applicability due to the permanent modifications made on cells. Alternatively, many endeavors have been made to develop surface engineering techniques that can circumvent the limitations of genetic modification. In this review, current methods of non-genetic cell surface modification, including chemical conjugations, polymeric encapsulation, hydrophobic insertion, enzymatic and metabolic addition, will be introduced. Moreover, cell surface engineering plausible for cardiac remodeling and the future prospective will be discussed at the end.

One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, the authors demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME.

A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here the authors describe a strategy to enhance cell therapy via the conjugation of adjuvant drug–loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, the authors elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. They also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.

Cell surface composition determines all interactions of the cell with is environment, thus cell functions such as adhesion, migration and cell-cell interactions are likely to be controlled by engineering and manipulating cell membrane. Cell membranes present a rich repertoire of molecules, therefore a versatile ground for modification. However the complex and dynamic nature of the cell surface is also a major challenge for cell surface engineering that should also involve strategies compatible with cell viability. Cell surface engineering by selective chemical reactions or by the introduction of exogenous targeting ligands can be powerful tools for engineering novel interactions and control cell function. In addition to chemical conjugation and modification of functional groups, ligands of interest to modify the surface of cells include recombinant proteins, liposomes or nanoparticles. Here, the authors review recent efforts to perform changes to cell surface composition.

Therapeutic treatments based on the injection of living cells are in clinical use and preclinical development for diseases ranging from cancer to cardiovascular disease to diabetes. To enhance the function of therapeutic cells, a variety of chemical and materials science strategies are being developed that engineer the surface of therapeutic cells with new molecules, artificial receptors, and multifunctional nanomaterials, synthetically endowing donor cells with new properties and functions. These approaches offer a powerful complement to traditional genetic engineering strategies for enhancing the function of living cells.

Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, the authors highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

Targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. Although macromolecules accumulate nonspecifically in tumors through the enhanced permeability and retention (EPR) effect, previous studies using nanoparticles to deliver chemotherapeutics or siRNA demonstrated that attachment of cell-specific targeting ligands to the surface of nanoparticles leads to enhanced potency relative to nontargeted formulations. Here, the authors use positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA.

Nanomaterials with precise biological functions have considerable potential for use in biomedical applications. Here the authors investigate whether multivalent attachment of small molecules can increase specific binding affinity and reveal new biological properties of such nanomaterials. The authors describe the parallel synthesis of a library comprising 146 nanoparticles decorated with different synthetic small molecules. Using fluorescent magnetic nanoparticles, they rapidly screened the library against different cell lines and discovered a series of nanoparticles with high specificity for endothelial cells, activated human macrophages or pancreatic cancer cells. Hits from the last-mentioned screen were shown to target pancreatic cancer in vivo. The method and described materials could facilitate development of functional nanomaterials for applications such as differentiating cell lines, detecting distinct cellular states and targeting specific cell types.

The work presented in this Thesis explores the feasibility of using a T cell carrier to transport model nanoparticles to the central nervous system (CNS). The use of non-phagocytic cells as carriers, such as T lymphocytes, for the transport of nanomaterials essentially relies on the attachment of the therapeutic cargo on their surface. Cell-surface modification is an emerging field of research with many opportunities for therapy. This work has also tried to address a more fundamental question encountered in this field and describes a novel methodology to precisely and quantitatively determine the localization of nanomaterials on the cell carrier after surface-conjugation.

Metal nanoparticles are widely used for the delivery and targeting of pharmaceutical, therapeutic and diagnostic agents in cancer therapy in recent years. The multifunctional nanoparticles constructed currently are supposed to show superior effects on cancer cells. This study was conducted to observe the difference between the effect of a biologically important peptide, silver (AgNPs) and gold (AuNPs) nanoparticles and their conjugates on two different cancer cells. Peptide (Boc-L-DP-L-OMe) was acquired from different sources and subjected to conjugation with biosynthesized gold and silver nanoparticles under standard conditions. These conjugates were tested against the colon cancer (HT-29) and breast cancer (MDA MB-231) cell lines. The results clearly depicted the improved activity of nanoparticles in the form of conjugates. Fluorescent dye microscopy and DNA fragmentation assay substantiate the fact that the conjugated nanoparticles cause higher level of disintegration of DNA in cells that consecutively damages and causes apoptosis due to lethality.

Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. This research shows the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments.

Natural cells have been explored as drug carriers for a long period. They have received growing interest as a promising drug delivery system (DDS) until recently along with the development of biology and medical science. The synthetic materials, either organic or inorganic, are found to be with more or less immunogenicity and/or toxicity. The cells and extracellular vesicles (EVs), are endogenous and thought to be much safer and friendlier. Furthermore, in view of their host attributes, they may achieve different biological effects and/or targeting specificity, which can meet the needs of personalized medicine as the next generation of DDS. In this review, the authors summarized the recent progress in cell or cell membrane-based DDS and their fabrication processes, unique properties and applications, including the whole cells, EVs and cell membrane coated nanoparticles.

Surface modification of living cells with natural or synthetic polymers is a powerful and useful tool in biomedical science and engineering. Various functional groups and bioactive substances can be immobilized to the cell surface through covalent conjugation, hydrophobic interaction, or electrostatic interaction. In this review, the authors provide an overview of the methods and polymers employed in cell surface modification, including: (1) covalent conjugation utilizing amino groups of cell surface proteins, (2) hydrophobic interaction of amphiphilic polymers with a lipid bilayer membrane, and (3) electrostatic interactions between cationic polymers and a negatively charged cell surface. The authors also discuss the applications in studies on cell therapy, cell–cell interaction analysis, cell arrangement, and lineage determination of stem cells.

The authors successfully conjugated biotin probes not only to mouse hematopoietic cells but also to yeast cells, 293T cells, and Toxoplasma gondii. Installation of single domain antibodies on activated CD8 T cell redirects cell-specific cytotoxicity to cells that bear the relevant antigen. Likewise, conjugation of Toxoplasma gondii with single domain antibodies targets the pathogen to cells that express the antigen recognized by these single domain antibodies. This simple and robust enzymatic approach enables engineering of the plasma membrane for research or therapy under physiological reaction conditions that ensure the viability of the modified cells.

The Lewis alpha (1-->3/4)-fucosyltransferase (Le-FucT) is known to fucosylate both Type I (beta Gal(1-->3) beta GlcNAc) and Type II (beta Gal(1-->4) beta GlcNAc) sequences even when these are sialylated at OH-3 or fucosylated at OH-2 of the terminal Gal residues. These acceptor sequences are ubiquitous on mammalian cell-surface glycoproteins and glycolipids. The Le-FucT enzyme is therefore a potential candidate as a universal reagent for the modification of cell surfaces. It is proposed that the Le-FucT represents a powerful new tool with the ability to label animal cell surfaces with preassembled oligosaccharide and possibly also other complex recognition markers.

To optimize live cell fluorescence imaging, the choice of fluorescent substrate is a critical factor. Although genetically encoded fluorescent proteins have been used widely, chemical fluorescent dyes are still useful when conjugated to proteins or ligands. However, little information is available for the suitability of different fluorescent dyes for live imaging. The authors here systematically analyzed the property of a number of commercial fluorescent dyes when conjugated with antigen-binding (Fab) fragments directed against specific histone modifications, in particular, phosphorylated H3S28 (H3S28ph) and acetylated H3K9 (H3K9ac). According to the authors‘ analysis, conjugation with green fluorescent dyes, like Alexa Fluor 488, has the least effect on Fab affinity and is the best for live cell imaging, although these dyes are less photostable than red fluorescent dyes.

This article is part of the Peptide Conjugates for Biological Applications special issue. Peptide and protein conjugates hold a prominent position in the area of bioconjugate chemistry. They have been the subject of intensive studies over the years, because of their high potential in, for example, the biomedical field. Furthermore, their functional richness and structural vulnerability makes efficient and selective conjugation of these biomolecules often a real endeavor. I have been involved in this highly active research field for a number of years already, and have seen it mature into an area where highly complex hybrid structures can be created. Still, with regard to both toolbox development and application of bioconjugation strategies much research is required.

The authors engineer cell membranes with β-cyclodextrin and subsequently manipulate cell behaviours via photo-responsive host-guest recognition. With this methodology, they demonstrate reversible manipulation of cell assembly and disassembly. The method enables light-controllable reversible assembly of cell–cell adhesion, in contrast with previously reported irreversible effects, in which altered structure could not be reused. They also illustrate the utility of the method by designing a cell-based therapy. Peripheral blood mononuclear cells modified with aptamer are effectively redirected towards target cells, resulting in enhanced cell apoptosis.

Adoptive therapy with regulatory T cells (Tregs) to prevent graft-versus-host disease (GVHD) would benefit from a strategy to improve homing to the sites of inflammation. The authors hypothesized that adding fucose to human Tregs, forming the Sialyl Lewis X moiety on P-selectin glycoprotein ligand-1, would improve their trafficking pattern. The selectin pathway recruiter, α-1,3-fucosyltransferase-VI enzyme, significantly increased Treg surface fucosylation (66% vs 8%). In a xenogenic GVHD mouse model, fucosylated Tregs showed prolonged periods of in vivo persistence. When given at a lower dose compared with the untreated Tregs, the murine recipients of fucosylated Tregs maintained weight, had ameliorated clinical GVHD, and improved survival (70% vs 30%; P < .0001). These preclinical data indicate that fucosylated human Tregs is an effective strategy for prevention of GVHD and, as such, warrants consideration for future clinical trials.

Core fucosylation is one of the most important glycosylation events in the progression of liver cancer. For this study, the authors used an easily handled L-fucose analog, 2-fluoro-L-fucose (2FF), which interferes with the normal synthesis of GDP-fucose, and verified its potential roles in regulating core fucosylation and cell behavior in the HepG2 liver cancer cell line. The results clearly described the roles of 2FF and the importance of core fucosylation in liver cancer progression, suggesting 2FF shows promise for use in the treatment of hepatoma.

The authors discuss the use of gene knockout studies, competitive inhibitors of fucose-containing glycan, and metabolic inhibitors of fucose biosynthesis to probe fucosylated glycan biosynthesis and signaling and its functional consequences. Promising clinical and preclinical applications in sickle cell disease, rheumatoid arthritis, tumor inhibition, metastasis prevention, antibody-dependent cell-mediated cytotoxicity, chemoresistance reversal, and in improving chemotherapy-related side effects and recovery are reviewed.

Lipids and DNAs are two major building blocks of life. Interestingly, by chemically linking these two natural compounds together, synthetic lipid-DNA conjugates exhibit several attractive features for cell membrane studies. These lipid-DNA conjugates are amphiphilic macromolecules combining the cell membrane insertion capability of lipids with the properties of DNAs in precise hybridization and programmability. These supramolecular conjugates have demonstrated exciting applications from generating cell membrane nanopores to transmembrane cargo deliveries, and from analyzing cell membrane events to tissue engineering. In this review, the authors will discuss the design, structures, and biological applications of lipid-DNA conjugates, with an emphasis on their functions on live cell membranes.

An apt modification: A simple and effective way to modify the cell surface with target‐specific ligands, such as DNA aptamers, while minimizing the effects on the modified cells has been developed. After incubating with lipo–aptamer probes, immune cells (red, see scheme) recognize and kill cancer cells (blue) in the cell mixture.

The authors report the bottom-up synthesis of microtissues composed of multiple cell types with programmed connectivity. They functionalized cells with short oligonucleotides to impart specific adhesive properties. Hybridization of complementary DNA sequences enabled the assembly of multicellular structures with defined cell–cell contacts. They demonstrated that the kinetic parameters of the assembly process depend on DNA sequence complexity, density, and total cell concentration. Thus, cell assembly can be highly controlled, enabling the design of microtissues with defined cell composition and stoichiometry. They used this strategy to construct a paracrine signaling network in isolated 3-dimensional microtissues.

Detection of small molecules or proteins of living cells provides an exceptional opportunity to study genetic variations and functions, cellular behaviors, and various diseases including cancer and microbial infections. The aim in this review is to give an overview of selected research activities related to nucleic acid-based aptamer techniques that have been reported in the past two decades. Limitations of aptamers and possible approaches to overcome these limitations are also discussed.