Rapid Single-Step Growth of MOF Exoskeleton on Mammalian Cells for Enhanced Cytoprotection

Mammalian cells are promising agents for cell therapy, diagnostics, and drug delivery. For full utilization of the cells, development of an exoskeleton may be beneficial to protecting the cells against the environmental stresses and cytotoxins to which they are susceptible. They report here a rapid single-step method for growing metal–organic framework (MOF) exoskeletons on a mammalian cell surface under cytocompatible conditions. The MOF exoskeleton coating on the mammalian cells was developed via a one-pot biomimetic mineralization process. With the exoskeleton on, the individual cells were successfully protected against cell protease (i.e., Proteinase K), whereas smaller-sized nutrient transport across the exoskeleton was maintained. Moreover, vital cellular activities mediated by transmembrane GLUT transporter proteins were also unaffected by the MOF exoskeleton formation on the cell surfaces. Altogether, this ability to control the access of specific molecules to a single cell through the porous exoskeleton, along with the cytoprotection provided, should be valuable for biomedical applications of mammalian cells.

Graphical Abstract

Mammalian cells such as stem cells can be promising agents for cell therapy, diagnostics, and drug delivery. However, because of the absence of a robust cell wall or exoskeleton, mammalian cells are sensitive to the subtle changes in their microenvironment such as osmotic pressure, nutrient level, and cytotoxins. It is, therefore, necessary for full utilization of the mammalian cells that they are protected and their viabilities are assured.

Schematic Illustration of Formation of MOF Exoskeleton

The field of artificial cell coating with mechanically durable materials has matured rapidly since the pioneering work in the early 2000s. Although early research humbly began by coating dead cells, it quickly evolved into coating of individual living cells.The synthetic strategies with various materials such as silicon dioxide, silicon dioxide-titanium dioxide, polydopamine, and iron-tannate coordination complex have been reported for the formation of cell-in-shell structures. Interestingly, these coating processes have offered degree of cytoprotection against various stresses such as UV–C radiation, lyticase, and toxic nanoparticles. However, complicated and time-consuming multistep processes for cell coating and poor control of the permeability of the coating have also been identified as weaknesses of the systems.Therefore, a simplified coating process would certainly be beneficial for reducing stress to the extremely labile mammalian cells.

Characterization of ZIF-8 nanoparticles synthesized in 1× PBS. (A) XRD patterns of ZIF-8 nanoparticles synthesized

Metal–organic frameworks (MOFs) are a class of porous materials that are constructed from metal nodes connected via organic linkers. Among them, zeolitic imidazolate frameworks (ZIFs), which consist of metal ions bridged tetrahedrally by imidazolate-type linkers, are often addressed in encapsulating various biomolecules such as proteins, insulin, and DNA because of its well-known biocompatibility, exceptional chemical stability, and the potential to be synthesized in pure water conditions. Another beneficial feature of ZIF is its high porosity; the highly porous property of ZIF allows delivery of small-sized molecules such as nutrients from the external environment to the encapsulated biomolecules through the microsized pores.Thus, recently, the concept has been extended from their use as matrices for encapsulating biomolecules to more complex systems like mammalian cells. For example, Zhu et al. have reported a cell-in-shell structure by linking separately synthesized ZIF nanoparticles (ZIF NP) onto the individual mammalian cell surface assisted by tannic acid as a chemical binder. Although ZIF NP-coated cells successfully demonstrated good cell viability under stressful conditions, the tannic acid treatment still induce stress on the cell and can possibly deteriorate the intrinsic porous properties of the MOF shell.

Development of ZIF-8-coated MDA-MB-231 cells.

d-Glucose permeability through the ZIF-8 exoskeleton layer.

Proof-of-concept demonstration of MOF-Janus cells.

An alternative approach to develop a MOF-coated cell is via biomimetic mineralization.

In this method, nucleation and growth of the MOF precursors are facilitated by a biomolecule-rich cell membrane; and cell coating is achieved in a rapid, single-step and binder-free manner. Thus, herein, they demonstrated the formation of protective ZIF-8 shell on individual human breast cancer cells (MDA-MB-231) as an artificial exoskeleton applying biomimetic mineralization approach. The well-known stability and biocompatibility of ZIF coating layer must protect the mammalian cells to enhance the tolerance in cytotoxic enzyme presenting environments. Furthermore, the highly porous nature of the ZIF layer allows the transport of small essential nutrients like glucose from its environment to the cells without disrupting the intrinsic function of transmembrane protein such as GLUT transporter. The formation of ZIF-based artificial exoskeleton on the mammalian cell will certainly be beneficial not only for the safe handling of the cells but also for biomedical applications.

  1. Rapid Single-Step Growth of MOF Exoskeleton on Mammalian Cells for Enhanced Cytoprotection Laura Ha, UnJin Ryu, Dong-Chang Kang, Jung-Kyun Kim, Dengrong Sun, Yong-Eun Kwon, Kyung Min Choi, and Dong-Pyo Kim ACS Biomaterials Science & Engineering Article ASAP DOI: 10.1021/acsbiomaterials.1c00539