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Ulcerative colitis (UC) remains a significant therapeutic challenge due to its complex pathogenesis involving oxidative stress, immune dysregulation, and gut microbiota dysbiosis. Melanin, a natural biopolymer with robust anti‐inflammatory and antioxidant properties, presents a promising treatment avenue for UC. Probiotics, particularly Escherichia coli Nissle 1917 (EcN), have gained recognition for their role in restoring gut homeostasis. In this study, we genetically engineered EcN to overexpress tyrosinase (EcN‐T), facilitating the biosynthesis of melanin specifically for UC treatment. The engineered probiotics demonstrated superior therapeutic efficacy compared to either melanin or EcN administered alone, highlighting a synergistic effect. EcN‐T not only exhibited significant capabilities in scavenging reactive oxygen species and restoring gut microbiota but also possessed the characteristic of enhancing gut colonization time, thereby extending the dosing frequency. Moreover, EcN‐T showcased novel mechanisms, such as the restoration of the intestinal mucosal barrier and the elevation of short‐chain fatty acid levels. Additionally, EcN‐T inhibited M1 macrophage polarization through Hypoxia‐Inducible Factor 1‐alpha (HIF‐1α)dependent glycolytic reprogramming, underscoring its immunomodulatory potential. Collectively, these findings provide new insights into the therapeutic potential of EcN‐T for UC treatment, offering a novel strategy that enhances treatment efficacy while potentially reducing side effects associated with conventional therapies.

Engineered probiotics are a kind of new microorganisms produced by modifying original probiotics through gene editing. With the continuous development of tools and technology progresses, engineering renovation of probiotics are becoming more diverse and more feasible. In the past few years there have been some advances in the development of engineered probiotics that will benefit humankind. This review briefly introduces the theoretical basis of gene editing technology and focuses on some recent engineered probiotics researches, including inflammatory bowel disease, bacterial infection, tumor and metabolic diseases. It is hoped that it can provide help for the further development of genetically modified microorganisms, stimulate the potential of engineered probiotics to treat intractable diseases, and provide new ideas for the diagnosis of some diseases or some industrial production.

Inflammatory bowel disease (IBD) is a chronic condition affecting the intestines, marked by immune-mediated inflammation. This disease is known for its recurrent nature and the challenges it presents in treatment. Recently, probiotic have gained attention as a promising alternative to traditional small molecular drugs and monoclonal antibody chemotherapies for IBD. Probiotic, recognized as a \"living\" therapeutic agent, offers targeted treatment with minimal side effects and the flexibility for biological modifications, making them highly effective for IBD management. This comprehensive review presents the latest advancements in engineering probiotic-based materials, ranging from basic treatment mechanisms to the modification techniques used in IBD management. It delves deep into how probiotic produces therapeutic effects in the intestinal environment and discusses various strategies to enhance probiotic's efficacy, including genetic modifications and formulation improvements. Additionally, the review addresses the challenges, practical application conditions, and future research directions of probiotic-based therapies in IBD treatment, providing insights into their feasibility and potential clinical implications.

Diabetes Mellitus (DM) is a substantial health concern worldwide, and its incidence is progressively escalating. Conventional pharmacological interventions frequently entail undesirable side effects, and while probiotics offer benefits, they are hindered by constraints such as diminished stability and effectiveness within the gastrointestinal milieu. Given these complications, the advent of bioengineered probiotics is a promising alternative for DM management. The objective of this review is to provide an exhaustive synthesis of the most recent studies on the use of engineered probiotics in the management of DM. This study aimed to clarify the mechanisms through which these probiotics function, evaluate their clinical effectiveness, and enhance public awareness of their prospective advantages in the treatment of DM. Scholarly critiques have explored diverse methodologies of probiotic engineering, including physical alteration, bioenrichment, and genetic manipulation. These techniques augment the therapeutic potency of probiotics by ameliorating gut microbiota, fortifying the intestinal barrier, modulating metabolic pathways, and regulating immune responses. Such advancements have established engineered probiotics as a credible therapeutic strategy for DM, potentially providing enhanced results compared to conventional treatments.

Listeriosis is a foodborne infection caused by Listeria monocytogene s that causes febrile gastroenteritis and central nervous system infections and that can often lead to fatality. Upon consumption of contaminated food, Listeria is able to survive a number of gastrointestinal stressors, including competition with the host microbiota. The emergence of antibiotic-resistant clones of L. monocytogene s, together with the side effects of antibiotic treatment, highlights the need for alternatives or additives for its treatment and prevention. Saccharomyces boulardii is a probiotic yeast that is often used alongside antibiotics to minimize side effects since it is not affected by them as a result of its eukaryotic nature. Furthermore, it can be engineered to produce a wide range of molecules. We previously engineered Saccharomyces cerevisiae through CRISPR-Cas9 integration to produce Ply511, a bacteriophage endolysin active against L. monocytogene s, showing the potential of engineered yeast to produce endolysins for biocontrol. In this study, we extended this approach to the probiotic yeast S. boulardii and directly compared the two yeasts as secretion hosts for Ply511. Using a simulated human gastrointestinal environment, we evaluated their ability to retain endolysin activity and reduce L. monocytogenes levels. We then tested the cell extracts from both yeasts in a bacterial consortium termed SImplified HUman intestinal MIcrobiota (SIHUMI), confirming a specificity for Listeria . Finally, we evaluated their activity in a simulated intestinal fermentation using fecal samples from human donors. Overall, this study demonstrates the potential of delivering endolysins to the gut via engineered probiotic S. boulardii. Key points CRISPR-Cas9-engineered S. boulardii and S. cerevisiae were compared, both allowing the expression and activity of endolysin Ply511 against L. monocytogenes. Endolysin Ply511 retained its activity against L. monocytogenes in simulated gastrointestinal digestion and was specific against Listeria in a bacterial consortium termed SImplified HUman intestinal MIcrobiota (SIHUMI). Using fecal samples from human donors, the anti-Listeria effect was reduced potentially due to the lower metabolic activity of S. boulardii and the higher competition with the intestinal microbiome. Graphical Abstract

Inflammatory bowel disease (IBD) is a chronic, relapsing condition that is often refractory to treatment. Data from the Global Burden of Disease Study (GBD) indicate that the incidence and disease burden of this condition continue to rise globally, posing a significant public health challenge. With advancements in synthetic biology, engineered probiotics constructed using gene-editing tools like CRISPR-Cas9 have offered a groundbreaking strategy for treating IBD. These engineered probiotics modulate the intestinal microenvironment with high precision through multiple mechanisms, including the targeted delivery of anti-inflammatory factors, scavenging of excess reactive oxygen species (ROS), restoration of barrier integrity, and regulation of microbial homeostasis. Preclinical studies indicate that, in terms of therapeutic precision and functionality, these probiotics may provide advantages over traditional medications. In addition, advances in delivery systems have improved acid resistance and targeted colonization at lesion sites. Engineered smart, responsive engineered probiotics can monitor inflammation in real-time and dynamically release therapeutic molecules. Their use in combination with conventional drugs can significantly improve mucosal healing. This study summarizes recent research progress of engineered probiotics in IBD diagnosis and treatment, aiming to provide insights into the application of microbiome-driven curative interventions in IBD.

Background/Objectives: Impaired intestinal barrier function is a hallmark of inflammatory bowel disease (IBD). Akkermansia muciniphila and its outer membrane protein Amuc_1100 can enhance this barrier, but the clinical application of Amuc_1100 is limited by the fastidious growth of its native host. This study aimed to overcome this by utilizing the robust probiotic Lacticaseibacillus paracasei L9 for targeted Amuc_1100 delivery. Methods: We engineered Lc. paracasei L9 to express Amuc_1100 via intracellular (pA-L9), secretory (pUA-L9), and surface-display (pUPA-L9) strategies. Their efficacy was assessed in Lipopolysaccharide (LPS)-induced macrophages and a dextran sulfate sodium (DSS)-induced colitis mouse model, evaluating inflammation, barrier integrity, and mucosal repair. Results: The secretory (pUA-L9) and surface-display (pUPA-L9) strains most effectively suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in macrophages. In mice, both strains alleviated colitis and outperformed native A. muciniphila in improving disease activity. Crucially, they exhibited distinct, specialized functions: pUA-L9 acted as a systemic immunomodulator, reducing pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), elevating anti-inflammatory mediators (IL-4 and IL-10), and promoting goblet cell differentiation; notably, the inhibitory effect of pUA-L9 on IL-6 expression was approximately 2-fold greater than that of pUPA-L9. In contrast, pUPA-L9 excelled in local barrier repair, uniquely restoring mucus layer integrity (Muc1, Muc2, and Tff3) and reinforcing tight junctions (ZO-1, Occludin, Claudin1, Claudin3, and Claudin4). In particular, pUPA-L9 increased Muc2 expression by approximately 3.6-fold compared with pUA-L9. Conclusions: We demonstrate that the subcellular localization of Amuc_1100 within an engineered probiotic dictates its therapeutic mode of action. The complementary effects of secretory and surface-displayed Amuc_1100 offer a novel, spatially targeted strategy for precision microbiome therapy in IBD.

Micro‐ and nanoplastics, particularly those derived from food‐contact materials like polyethylene terephthalate (PET), can damage gut barriers, making the gastrointestinal system more vulnerable to inflammation and infections. Here, a probiotic‐based drug delivery system (EcNT@L) is devised to mitigate nanoplastics‐induced gut barrier dysfunction by modulating gut immunity and microbiota. Escherichia coli Nissle 1917 (EcN) is genetically engineered to produce transforming growth factor‐β (TGF‐β) and then modified with an Eudragit L100‐55 coating. This engineered probiotic acts as an in vivo “drug factory”, exerting anti‐inflammatory and immune‐regulatory effects, with improved retention and bioavailability in the gastrointestinal tract. EcNT@L effectively protects Caco‐2 cells from inflammation and infections induced by nano PET, primarily by activating the NF‐κB signaling pathway. Besides, EcNT@L demonstrates superior in vivo therapeutic efficacy in treating gastrointestinal infection caused by the combined presence of nano PET and Salmonella, outperforming commercial antibiotics due to its ability to modulate immune responses and gut microbiota. This study highlights the potential of probiotic‐based drug delivery systems in addressing nanoplastics‐induced gut dysfunctions, offering a promising strategy for mitigating the environmental impact of micro‐ and nanoplastics. Intestinal barrier stability is vital for gut health. Plastic polyethylene terephthalate (PET) disrupts this barrier, causing inflammation and infections. This study encodes transforming growth factor‐β into EcN and modifies its surface with pH‐responsive polymer (EcNT@L), creating an oral drug delivery system to repair nano PET‐induced intestinal damage.

Akkermansia muciniphila (A. muciniphila), a mucin-degrading commensal bacterium predominant in the gut microbiota, establishes a multifaceted antioxidant defense system through its enzymatic machinery and bioactive metabolites. The bacterium maintains mucosal homeostasis via specialized mucinolytic enzymes while secreting functionally diverse components including SCFAs, outer membrane proteins (notably Amuc_1100), and extracellular vesicles (EVs). Mechanistically, Amuc_1100 enhances SOD activity and reduces oxidative damage markers such as MDA through TLR2/NF-κB pathway activation. SCFAs mediate systemic antioxidant responses via gut-organ axis communication, while EVs ameliorate intestinal barrier dysfunction through MAPK signaling pathway modulation. Clinically, A. muciniphila supplementation demonstrates therapeutic efficacy in improving insulin sensitivity in obese and type 2 diabetic patients, and shows potential in mitigating Parkinson's disease pathology by regulating α -synuclein oligomerization. Translational applications face several challenges, including strain-specific functional variations, host microenvironment dependencies, and potential risks of excessive mucin degradation. Recent advances in bioengineering approaches, particularly microencapsulation and biomimetic delivery systems, have significantly enhanced bacterial viability and targeted delivery. Future investigations should employ integrated multi-omics strategies to elucidate the intricate metabolic-immune-redox regulatory networks of A. muciniphila, facilitating its development as a precision therapeutic intervention.

Abstract Research shows that the microbiome of the skin is present as an active contributor to wound healing processes by moving past its historical infection-related function. The review investigates how commensal and probiotic bacteria affect immunomodulation while accelerating epithelial growth, together with tissue repair processes. Researchers use modern methods to link immunological concepts with material science along with synthetic biological techniques to study engineered probiotics which transform current wound treatments. The research study represents an extensive integration of recent findings concerning probiotic-mediated immunomodulatory operations and engineered approaches that improve probiotic delivery systems and their performance during skin wound healing procedures. Recent genetically engineered Lactobacillus reuteri strains that express chemokines like CXCL12 have been found to promote wound healing to an accelerated rate in animal models, and pre-clinical phases of clinical trials in the setting of diabetic foot ulcers (DFU) has demonstrated safety and therapeutic potential. Simultaneously, another live biotherapeutic product has been validated in terms of regenerative and immunomodulatory properties in animal models and in a clinical trial, a multi-cytokine-integrated strain of Lactococcus cremoris secreting FGF-2, IL-4, and CSF-1 promoted faster wound healing in diabetic mice and healed 83% of subjects in a Phase I DFU study. The range of probiotic therapies for trauma care expands due to advancements in probiotic delivery using materials and membrane vesicles derived from probiotics. This review builds a detailed framework that connects core immune functions with modern engineering methods for developing smart wound healing systems that combine engineered probiotics with bioresponsive materials and real-time monitoring systems. Engineered probiotics promise to become an alternative strategy for treating chronic wounds and infection-related complications that currently create significant medical problems. Graphical Abstract Graphical Abstract