JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

Bacteriophage engineering: from serendipitous hunting to rational design in therapeutics and microbiome modulation

Author(s): Shujie XU¹, Xianglin FEI¹, Guangyao WANG¹, Shijiao HUAN², Ziyue WU², Aikun FU^1, ³
Affiliation(s): 1Key Laboratory of Animal Nutrition and Feed in East China, Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Feed Science Institute, College of Animal Science, Zhejiang University (Zijingang Campus), Hangzhou 310058, China 2Wuhan University of Technology, College of Chemistry, Chemical Engineering and Life Sciences, Wuhan 430070, China 3ZJU-Xinchang Joint Innovation Centre (TianMu Laboratory), Gaochuang Hi-Tech Park, Xinchang 312500, China
Corresponding email(s): Aikun FU, aikunfu@zju.edu.cn
Key Words: Phage engineering; Synthetic biology; CRISPR-Cas; Genome rebooting; Therapeutic development

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Shujie XU¹, Xianglin FEI¹, Guangyao WANG¹, Shijiao HUAN², Ziyue WU², Aikun FU^1,³. Bacteriophage engineering: from serendipitous hunting to rational design in therapeutics and microbiome modulation[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500859

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author="Shujie XU¹, Xianglin FEI¹, Guangyao WANG¹, Shijiao HUAN², Ziyue WU², Aikun FU^1,³",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500859"
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Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: Phage engineering has transitioned from rudimentary genetic modifications into a highly sophisticated discipline that is capable of generating bespoke therapeutic agents. This review systematically evaluates the modern engineering toolbox in this field, spanning high-efficiency CRISPR-Cas systems (Cas9, Cas12, and Cas3) and novel recombitrons designed for counter-selection-free multiplex editing. Building upon these precise editing capabilities, we explore the paradigm shift toward de novo genome writing and artificial intelligence (AI)-driven design (e.g., Evo), while offering a critical assessment of current bottlenecks, such as the reported 5.3% experimental success rate and training data biases. Beyond genomic alterations, we explore phage display and chemical conjugation as parallel strategies for functionalization. Furthermore, we analyze the 'lytic paradox' in microbiome modulation-specifically regarding the restoration of short-chain fatty acid (SCFA) production-and outline essential biocontainment frameworks, such as synthetic 'kill-switches,' that are necessary for clinical translation. Ultimately, the convergence of synthetic biology and AI is poised to catalyze next-generation solutions against antimicrobial resistance and metabolic disorders.

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