Commensal microbes—especially those in the gut, skin, and oral cavity—are rapidly becoming programmable living therapeutics. With precise genome engineering and host-aware design, engineered strains can sense disease signals, produce bioactive molecules, modulate immunity, and restore microbial balance. To move from proof-of-concept to clinic, the field must prioritize safety, genomic stability, biocontainment, and manufacturability. This Research Topic invites work that enables safe, stable genetic programming of commensal microorganisms for reliable, ethical use in human health.

Commensals are shifting from passive inhabitants to active therapeutic platforms capable of delivering small molecules, peptides, enzymes, and nucleic-acid-based payloads with spatial and temporal control. Translation, however, requires understanding how engineered functions perform over time within complex host environments.

Safety is paramount. Engineered commensals must avoid off-target editing, unintended immunogenicity, and horizontal gene transfer. Heterogeneous host niches—fluctuating pH, bile salts, nutrients, and immune pressures—can reshape expression, fitness, and stability beyond in vitro predictions. Ensuring circuits remain controllable, reversible, and confined motivates robust biocontainment, scarless or DNA-free editing, and validated assays for shedding and environmental persistence.

Genetic and functional stability is equally critical. Therapeutic circuits face evolutionary pressures against burdensome traits. Approaches such as neutral-site integration, copy-number control, toxin–antitoxin stabilization, and chassis streamlining can reduce escape while maintaining potency. Longitudinal measurements in organoids, gut simulators, gnotobiotic models, and early human studies are essential to quantify mutation rates, fitness trade-offs, and durability.

Responsible translation also demands clear regulatory and ethical frameworks. Standardized safety metrics, harmonized reporting for gene transfer and containment, and transparent risk–benefit assessments should guide trials and post-release monitoring. Proactive attention to consent, reversibility, long-term microbiome surveillance, data privacy, equity, and environmental stewardship will accelerate safe adoption.

Scope

Safe genome editing platforms (CRISPR/Cas, base/prime editors, integrases; off-target minimization; kill-switches and multilayer biocontainment)

Genetic stability and evolutionary robustness (neutral-site integration, copy-number control, circuit minimization, recoding to reduce HGT; in vivo tracking)

Host–microbe and community-aware design (context-aware promoters, quorum sensing, nutrient-responsive control; ecological interactions and immunogenicity)

Therapeutic functions and delivery (in situ biologics, metabolite modulation, biosensing-to-actuation; inducible dosing and external control)

Analytics, standards, and regulatory science (gut simulators, organoids, gnotobiotic models; standardized assays for HGT/shedding; safety benchmarks)

Manufacturing and clinical translation (GMP strain development, formulation and stability, colonization kinetics, phage susceptibility; clinical trial design and monitoring)

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Programmable Living Therapeutics: Safe and Stable Genome Editing in Commensal Strains