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Research Highlights

Cell Surface Engineering and Application in Cell Delivery to Heart Diseases

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Cell therapy has become an attractive reagent for advanced therapeutic strategies because of its strong secretory cell function, differentiation capability, specific homing effects through chemotaxis, distinctive therapeutic potentials, and ex vivo expandability, further expanding its influence in the areas of cell-based therapy such as cancer immunotherapy, regenerative medicine, and tissue engineering.

Although cell therapy has emerged as a superior therapeutic strategy, the use of cells as therapeutic agents in regenerative medicine and cancer immunotherapy has, unfortunately, presented difficulties in controlling cell function to maximize therapeutic benefits. However, studies have shown that cell surface engineering, involving genetic engineering and non-genetic engineering, is undoubtedly a powerful tool for controlling cell function. Genetically engineered cells may show inconsistent and unpredictable therapeutic efficacy because genetic engineering does not apply to all types of cells, especially stem cells and slowly dividing cells. Compared with genetic engineering, non-genetic engineering reduces genetic integration risks, alleviates safety risks in clinical settings, and improves transduction/transfection efficiency. Research suggests that non-genetic surface engineering has many advantages such as adding new functions, reducing graft rejection for transplantation, creating a heterogeneous cluster of cells by cell-to-cell attachment, enhancing immune effector functions, and programming cell-to-cell interactions.

Non-genetic cell surface engineering techniques, such as covalent conjugation, electrostatic interactions, hydrophobic insertion, offer more transient and reversible modifications to control cellular functions. In more detail, covalent conjugation refers to the attachment of a bioactive substance to the cell membrane by chemical, metabolic, or enzymatic action. Chemical conjugation is the most direct method, which uses exposed functional groups on the surface of membrane proteins as grafting points. At present, Nhydroxylsuccinimidyl ester groups (NHS), maleimide, and pyridyldithiol are the most commonly used chemical cross-linkers. Although its conjugation to biomaterials will gradually disappear over time, the surface modified by covalent conjugation is stable relative to other genetic engineering methods. Alternatively, electrostatic interaction modifies the cell surface by creating a self-assembled structure between the negatively charged cell surface and the cationic polymer. Surface engineering by electrostatic interaction of the major advantage is that by non-invasive encapsulation, can avoid the cell under the influence of pure stress and immune response. However, the biocompatibility of cationic polymers should be addressed before used for cell therapy.

Unlike Covalent conjugation and electrostatic interaction, surface modification of membrane-anchored bioactive molecules by hydrophobic insertion allows them to participate in the dynamic motion of the cell membrane. In the process, molecules of interest must be hydrophobized by lipid or alkyl chain conjugation and the retention time on the surface is variable, but hydrophobic insertion is still an attractive surface engineering technology, available to almost all types of cells quickly and nontoxic surface modification.

Currently, regenerative therapies employing stem cells, especially MSCs, through cell-based therapies attempts to stimulate endogenous regeneration mechanisms have enormous clinical application potential treatment of cardiac diseases. Even without study clearly shows that physical replacement of cardiomyocytes may be the essence of stem cell therapy for heart injury, and a method of improving the clinical outcome of stem cell therapy is to develop a specifically targeted disease site within the therapeutic time window competent delivery method. In this aspect, cell surface engineering provides effective means by enhancing the targeting of MSCs or any discovered therapeutic cells or stem cells without altering their native function. Moreover, to exploit the SDF-1 gradient for targeted delivery of MSCs to the MI site, pre-expanded MSCs should be rapidly modified through the targeted moiety, and hydrophobic cell surface engineering provides an ideal solution to enhance the homing of MSCs to the injured myocardium. By hydrophobic insertion of modified cells, the specialized therapeutic MSCs are produced instantaneously without harmful effects because it is a non-invasive engineered cell and the cell membrane can be easily modified by therapeutic molecules containing lipophilic anchors.

To date, the surface of engineered living cells still faces some challenges, including improving the surface residence time of the desired biomaterials to prolonged therapeutic effects, mandatory satisfaction with several basic principles of biocompatibility, and threats from in vivo system complexity. However, cell surface engineering still has a variety of applications in biomedicine, especially with good development potential and plausibility in terms of cardiac remodeling.

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