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Review
. 2023 Jul;13(7):e1244.
doi: 10.1002/ctm2.1244.

Boolean logic in synthetic biology and biomaterials: Towards living materials in mammalian cell therapeutics

Affiliations
Review

Boolean logic in synthetic biology and biomaterials: Towards living materials in mammalian cell therapeutics

Eric M Bressler et al. Clin Transl Med. 2023 Jul.

Abstract

Background: The intersection of synthetic biology and biomaterials promises to enhance safety and efficacy in novel therapeutics. Both fields increasingly employ Boolean logic, which allows for specific therapeutic outputs (e.g., drug release, peptide synthesis) in response to inputs such as disease markers or bio-orthogonal stimuli. Examples include stimuli-responsive drug delivery devices and logic-gated chimeric antigen receptor (CAR) T cells. In this review, we explore recent manuscripts highlighting the potential of synthetic biology and biomaterials with Boolean logic to create novel and efficacious living therapeutics.

Main body: Collaborations in synthetic biology and biomaterials have led to significant advancements in drug delivery and cell therapy. Borrowing from synthetic biology, researchers have created Boolean-responsive biomaterials sensitive to multiple inputs including pH, light, enzymes and more to produce functional outputs such as degradation, gel-sol transition and conformational change. Biomaterials also enhance synthetic biology, particularly CAR T and adoptive T cell therapy, by modulating therapeutic immune cells in vivo. Nanoparticles and hydrogels also enable in situ generation of CAR T cells, which promises to drive down production costs and expand access to these therapies to a larger population. Biomaterials are also used to interface with logic-gated CAR T cell therapies, creating controllable cellular therapies that enhance safety and efficacy. Finally, designer cells acting as living therapeutic factories benefit from biomaterials that improve biocompatibility and stability in vivo.

Conclusion: By using Boolean logic in both cellular therapy and drug delivery devices, researchers have achieved better safety and efficacy outcomes. While early projects show incredible promise, coordination between these fields is ongoing and growing. We expect that these collaborations will continue to grow and realize the next generation of living biomaterial therapeutics.

Keywords: CAR T cells; biomaterials; boolean logic; cell therapy; drug delivery; synthetic biology.

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Conflict of interest statement

E.M.B., S.A., Y.L.C., W.W. and M.W.G. are co‐inventors on a patent application, and the application is available for licensing.

Figures

FIGURE 1
FIGURE 1
Collaborative advances in synthetic biology and biomaterials. (A) Synthetic biology confers control over therapeutic systems via Boolean logic and inducibility. Shown is a split chimeric antigen receptor (CAR) T cell that exhibits AND gate Boolean logic by splitting activation signals, requiring both for activation (figure adapted from Cho et al.) (left) and recombinase‐based inducible gene circuits (figure adapted from Weinberg et al.) (right) (B) Biomaterials offer biocompatibility via pegylation, encapsulation, biomimicry and rational design. Biomaterials also confer enhanced biodistribution and pharmacokinetics through targeted therapies and controlled release systems. (C–E) Existing technologies that harness strengths of both synthetic biology and biomaterials include (C) synthetic Boolean‐responsive nanoparticles (adapted from Zhang et al.), (D) CAR T cell‐releasing scaffolds (adapted from Grosskopf et al. and Agarwalla et al.), and (E) encapsulated designer cell therapies.
FIGURE 2
FIGURE 2
Building programmable, Boolean‐responsive biomaterials using stimuli‐responsive domains. (A) Stimuli responsive biomaterials utilize many inputs to achieve outputs via modulating the physical and chemical properties of the material. (B) YES gates in biomaterials often display leaky output. (C) AND gates are designed for simultaneous release, but many biomaterial AND gates utilize sequential release to match conditions of a physiologic scenario. (D) OR gates ideally exhibit all‐or‐nothing responses, but often result in additive responses instead, where presence of both signals leads to a larger effect. (E) Stimuli responsive materials usually respond in a concentration dependent manner, which emulates an analog signal. Digital signaling requires a single output strength regardless of input concentration. (F) An expansile nanoparticle releases cargo only when exposed to low pH. Adapted from Griset et al. (G) Polyethyleneimine‐CpG (PEI‐CpG) NPs loaded by adsorption into hydrogel/cryogel formulations, which are (H) synthetic polymers with cleavable domains create YES, OR, AND, and stacked logic gates. (I) Logic‐gated polymers from (G) are used as cleavable linkers in a hydrogel to enable logic‐gated degradation. (H and I) Adapted from Badeau et al. All data represented are idealized.
FIGURE 3
FIGURE 3
Synthetic biology improved with biomaterials. (A) Synthetic biology uses tools to build functionality into cells based on physiologic or synthetic inputs. This toolbox is employed via gene insertion, genetic circuits, protein circuits (adapted from Gao and Chong et al.), and/or multicellular computing (adapted from Tamsir et al.), and it enables synthesis, cell fate determination, communication, proliferation, and migration. (B) Traditional chimeric antigen receptor (CAR) T cells form YES gates that activate in response to a specific antigen. Boolean‐gated CAR T cells activate only in response to combinations of antigens, which enhances sensitivity and specificity. Common logic gates include OR (either antigen activates the CAR), AND (both antigens necessary to activate the CAR), and NIMPLY (one antigen activates the CAR, but another overrides and inhibits the activation). (C) A synthetic amphiphilic ligand acts as a cancer vaccine that homes to lymph nodes and inserts itself into the membrane of dendritic cells. An OR‐gated CAR T cell is primed with the vaccine and then exhibits potent cytotoxicity against tumour cells (adapted from Ma et al.). (D) Designer cells are encapsulated in alginate microbeads, which confer immune protection and selective permeability to prevent an inflammatory and fibrotic reaction while allowing physiologic sensing and therapeutic output (adapted from Xie et al.).
FIGURE 4
FIGURE 4
Living materials made from mammalian cell‐biomaterial hybrids. Existing technologies are converging on living material implants, which sense and respond to physiologic or pathologic stimuli and change internal properties and output based on these sensing mechanisms. Living material systems would feature response modules, which facilitate interaction between cell and biomaterial, biomaterial and environment, and environment and cell to dynamically respond and change form.

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References

    1. Huebsch N, Mooney DJ. Inspiration and application in the evolution of biomaterials. Nature. 2009;462:426‐432. - PMC - PubMed
    1. Ratner BD, ASH FJS, Lemons JE. Biomaterials Science: An Introduction to Materials in Medicine. 2nd ed. Elsevier Academic Press; 2004.
    1. Gardner TS, Cantor CR, Collins JJ. Construction of a genetic toggle switch in Escherichia coli. Nature. 2000;403:339‐342. - PubMed
    1. Elowitz MB, Leibler S. A synthetic oscillatory network of transcriptional regulators. Nature. 2000;403:335‐338. - PubMed
    1. Ratner BD, Zhang G. A history of biomaterials. In: Wagner WR, Sakiyama‐Elbert SE, Zhang G, Yaszemski MJ, eds. Biomaterials Science. 4th ed. Academic Press; 2020:21‐34.

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