'Living Medicines' for the Gut: How Engineers Are Turning Probiotics into Smart Biomaterials to Fight IBD

Ulcerative colitis and Crohn’s disease are increasingly being treated, but a safe “bullet” that is precise, gentle, and long-lasting has been missing. A new review in Theranostics suggests that engineered probiotics are a candidate: live microorganisms “packaged” in smart shells or genetically engineered to secrete anti-inflammatory molecules and repair the mucosal barrier. The authors systematize dozens of approaches—from hydrogels that respond to inflammation to bacteria that deliver therapeutic proteins—and carefully boil them down to practical scenarios for patients with inflammatory bowel disease (IBD).

Background of the study

GBD estimates that more than 6.8 million people worldwide live with IBD, and the incidence continues to rise in countries undergoing rapid urbanization. This places a strain on the healthcare system and makes it urgent to find safer and more convenient long-term therapies.

• Standard of care and its limitations. The drug “pillars” today are 5-ASA, GCS, immunomodulators, biological drugs (anti-TNF, anti-integrin, anti-IL-12/23) and JAK inhibitors. But some patients do not respond to induction, many experience loss of response, and systemic side effects and cost remain a problem. This pushes for locally acting and more gentle approaches.
• Why look at the microbiota and barrier “repair”. In IBD, dysbiosis, disruption of mucus and tight junctions of the epithelium, hyperactivation of TLR/NF-κB and oxidative stress are observed. Hence the idea of a therapy that restores the barrier, modulates the immune response and corrects the microbial composition - something that well-designed probiotics can potentially do.
• The problem of delivering live bacteria. The oral-intestinal tract is a hostile environment: acid, bile salts, enzymes, a layer of mucus, immune traps. Without protection, "live" agents die or do not reach the colon in the required quantity, so smart carriers are needed that are resistant to pH/bile and open precisely at the site of inflammation.
• What materials and synthetic biology offer. Modern approaches combine:
  • Hydrogels and capsules (alginate, pectin, HA, chitosan), including those sensitive to ROS/NO/H₂S, to “open” during inflammation;
  • Surface modifications for better adhesion to the mucous membrane;
  • Genetically tuned strains ( E. coli Nissle, Lactobacillus/Lactococcus) that synthesize IL-10, anti-TNF factors, antioxidant enzymes, etc.;
  • Combination platforms - bacteria + nanoparticles/drug. These directions are systematized in the Theranostics review.
• Regulatory framework for “live biopreparations”. Clinical translation is focused on stability, standardization of production and biosafety (genetic “switches”, colonization control). For such Live Biotherapeutic Products (LBP), the FDA has issued separate recommendations on CMC information in early stages of research, which forms requirements for the quality and traceability of strains.
• What is the benefit of this review? It brings together the disparate advances in materials science and synthetic biology into a practical map of the field: what mechanisms of action do engineered probiotics have, what carriers are already working in animal models of IBD, what bottlenecks (dose, colonization duration, safety) are hindering the transition to patients. This sets the agenda for further preclinical and clinical research.

Why is this important?

Classic IBD therapy regimens (5-ASA, steroids, anti-TNF, JAK inhibitors) do not help everyone and often cause systemic side effects. Engineered probiotics promise local, gentle and long-term therapy: bacteria colonize inflamed areas, act on site and work “on demand” when inflammation markers are high.

How 'Living Materials' Heal the Gut

The review identifies four key mechanisms of action:

• Immunomodulation - shifting the response towards anti-inflammatory cytokines and Tregs; weakening TLR/NF-κB signaling.
• Antioxidant effect – activation of the NRF2 pathway and neutralization of ROS in inflammatory foci.
• Barrier repair – strengthening tight junctions, stimulating the production of mucins and short-chain fatty acids (SCFAs).
• Control of microbiocenosis - suppression of pathogens by bactericins and their displacement through competition for adhesion.

Engineering Strategies: From "Carapaces" to Gene Tuning

1) Smart shells and carriers.
Prebiotic and polymer hydrogels shield bacteria from the acidic environment of the stomach and release them only in the colon. There are systems that “sense” NO, ROS or H₂S — inflammation molecules — and open up exactly where therapy is needed. Alginate, hyaluronic acid, pectin, chitosan, fibrous matrices and even 3D-printed structures are used.

2) Surface modifications.
Polysaccharides and adhesion peptides (biorthogonal conjugations) are “sewn” to bacteria, reactive nanocoatings are applied - this increases survival, targeted adhesion to the mucosa and delivery of useful metabolites.

3) Genetic engineering.
Strains (often E. coli Nissle 1917, Lactobacillus/Lactococcus) are configured to synthesize IL-10, anti-IL-1β/-TNF factors, antioxidant enzymes, inflammation sensors and molecules that restore redox balance - in animal models, this already reduces the activity of colitis.

4) Combined platforms.
Bacteria + nanoparticles/drug inside a “capsule”: this is how the effects of live therapy and controlled drug release are combined. In a number of studies, hyaluronate coating directs the structure specifically to the inflamed mucosa.

Which is closer to the clinic

The authors examine in detail the commercial multi-strain products VSL#3® and LGG® as references for formulation and delivery (capsules, microcapsules, cryo-drying) and compare them with more “advanced” engineering assemblies. The idea is to transfer the developed solutions for stability and dosing to a new generation of living biomaterials.

Problems that still need to be solved

• Stability and Dosage: Maintain viability, control colonization, and ensure a reproducible dose at each administration.
• Accuracy and safety. Eliminate horizontal gene transfer, unpredictable immune effects and dysbiosis.
• Manufacturing and regulation. Scalable “clean” processes and compliance for live biotherapeutic products (LBP) – without these, clinical translation will be slow. The review suggests specific ways – cultivation standards, strain tracking, “safety switches”.

Where is the field heading?

The trend is clear: a shift from dietary supplement-like probiotics to rationally designed “living drugs” aided by materials and synthetic biology. On the horizon are personalized cocktails for the patient’s microbiota, sensor strains that turn on therapy only when inflammation flares up, and “bacteria-carrier + drug” platforms that can maintain remission for months.

Source: Sang G. et al. Engineered Probiotic-Based Biomaterials for Inflammatory Bowel Disease Treatment. Theranostics. 2025;15(8):3289-3315. doi:10.7150/thno.103983