Chronic inflammatory conditions affect approximately 51.8% of adults in the United States, with 27.2% of individuals experiencing multiple chronic conditions (Boersma et al., 2020). These range of conditions include inflammatory bowel disease (IBD), heart disease, diabetes, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune disorders, degenerative disorders, and even cancer (Furman et al., 2019; Roth, 2018). Collectively, chronic inflammatory diseases account for over 50% of deaths worldwide (Furman et al., 2019; Roth, 2018).

IBD is a chronic, relapsing inflammatory disorder of the gastrointestinal tract and represents a major form of chronic intestinal inflammation, with a rapidly evolving global epidemiology (Wang et al., 2023; Yang et al., 2025). It primarily manifests as ulcerative colitis (UC) or Crohn’s disease (CD), distinguished by differences in disease location, histopathology, and clinical presentation. Recent comprehensive reviews have discussed these conditions in detail, including their pathogenesis, diagnosis, and therapeutic management (Appiah et al., 2025; Eltantawy et al., 2023; Seyedian et al., 2019). Here, we summarize the key distinctions between UC and CD in Table 1 to provide a concise snapshot of their defining features, drawing on these published studies.

Recent studies increasingly associate perturbed gut microbiota referred to as dysbiosis as a potential root cause of chronic inflammatory conditions. This imbalance often originates in the gut and then influences systemic inflammation, promoting diseases beyond the gastrointestinal tract (Buttó and Haller, 2016) (Figure 1). When inflammation persists over a prolonged period, it often leads to severe and life-threatening health conditions.

Several factors have been identified as triggers of gut dysbiosis including poor diet, obesity, disrupted sleep, chronic infections, stress, lack of physical activity, exposure to pollutants or chemicals, frequent antibiotic use, use of nonsteroidal anti-inflammatory drugs (NSAID), and tobacco use (Furman et al., 2019) (Figure 1). These triggers can disrupt gut microbial balance, initiate inflammation in the gut, and eventually contribute to systemic inflammatory conditions. Inflammation is the immune response to injury, toxins, or infections (Ansar and Ghosh, 2016) and involves the activation of inflammatory cells and signaling pathways to eliminate external or internal insults (Chen et al., 2018). A key component of this process is the generation of reactive oxygen species (ROS), which plays a critical role in inflammatory diseases, including those of the gastrointestinal (GI) tract.

When the gut’s mucosal barrier and environment is compromised by inflammatory triggers, the innate immune system responds rapidly, initiating an acute inflammatory response in the lamina propria. Polymorphonuclear leukocytes (PMNs) are recruited to the site of infection or damage, where these cells engulf pathogens and release ROS, enzymes, and vasoactive and pro-inflammatory substances (Mittal et al., 2014). While ROS generation can help resolve inflammation by creating a hypoxic environment through oxygen depletion to activate anti-inflammatory pathways (Campbell et al., 2014), excessive and prolonged oxidative stress marked by an imbalance between ROS production and antioxidant defense can result in apoptosis and tissue damage (Rezaie et al., 2007). The chronic inflammatory state arises when immune cells and pathways remain persistently activated even in the absence of external threats. If left unchecked for months or years, this chronic inflammation can impair organ and tissue function (Oronsky et al., 2022). Therefore, the elevated levels of pro-inflammatory markers and ROS are linked to the development of numerous diseases, including cancer, atherosclerosis, diabetes, arthritis, and cognitive decline (Furman et al., 2019; Ranneh et al., 2017). Given the profound health consequences associated with chronic gut inflammation, early diagnosis, management, and treatment are essential for maintaining overall health and preventing long-term complications.

In this review, we briefly outline current diagnostic and therapeutic approaches for chronic inflammatory gut conditions and discuss their limitations. We then describe recent advances aimed at addressing these challenges, with particular emphasis on emerging nanomedicine-based and smart, responsive therapeutic strategies. Promising studies that integrate diagnostic and therapeutic functionalities are highlighted, underscoring their potential to improve disease monitoring and enable personalized treatment. We also discuss the key barriers to translating these emerging approaches into clinical application in humans.

Nanomedicine utilizes nanoscale (10⁻⁹ m) molecules and structures to deliver therapies for diagnosis, and treatment of various disease conditions (Bayda et al., 2020; Huang et al., 2024; Mansoori and Soelaiman, 2005). Various studies have explored the application of nanotechnology in medicine. For example, nanoparticles (NPs) have been used as vaccine carriers and adjuvants, enhancing immunogenicity, achieving targeted delivery, improving bioavailability, and directly combating pathogens and inflammation (Azócar et al., 2019; Huang et al., 2024).

Various types of NPs have been explored for the diagnosis and treatment of IBD due to their ability to provide a stable and protective environment for encapsulated agents, shielding them from enzymatic degradation and the acidic conditions of the stomach (Date et al., 2016; Lundquist and Artursson, 2016; Zhang and Merlin, 2018; Stojanov and Berlec, 2024; Zhao et al., 2025). This property is particularly advantageous for targeted drug delivery to the inflamed intestine, where it can enhance therapeutic efficacy and reduce dosing frequency. Based on their composition and source, NPs can be broadly classified into lipid-based bilayer NP, polymeric NP (e.g., PLGA, chitosan), hydrogel-based NP, exosome-derived NP, and metallic NP (Stojanov and Berlec, 2024; Zhao et al., 2025). Each nanoparticle class exhibits distinct advantages and limitations, briefly summarized in Table 2 and discussed in detail previous reviews (Yue et al., 2023; Chen and Li, 2025; Fei et al., 2022; Laroui et al., 2013; Jiang et al., 2024).

In diagnostic imaging, dextran-coated cerium oxide NPs have been reported as a novel CT contrast agent for GI track imaging in patients with and without IBD. These NPs not only enhance imaging but also protect intestinal cells from oxidative damage, offering greater stability, biocompatibility, and target specificity toward inflammation sites compared to conventional CT contrast agents like iodinated small molecules or barium sulfates (Naha et al., 2020). Additionally, the co-administration of silymarin and selenium NPs in a rat model of colitis showed a promising antioxidant effect, reducing NF-κB-mediated proinflammatory cytokine production (Miroliaee et al., 2011). Another study engineered NPs to deliver the anti-inflammatory tripeptide (Lys-Pro-Val) directly to the colon in a murine colitis model. These NPs successfully released near the colonocytes, protecting against inflammatory responses (Laroui et al., 2010). Such studies demonstrate that NPs can serve as multifunctional drug delivery systems, modifiable in various ways to enhance treatment for IBD and other chronic inflammatory conditions.

Ongoing research is investigating the use of nanosensors and nanoprobes for detection, monitoring, and imaging of inflammatory lesions (Liu et al., 2024). However, concerns regarding the toxicity and bioaccumulation of inorganic NPs (such as gold, silver, and iron oxide) have prompted researchers to explore organic nanomaterials, including polymers, dendrimers, and liposomes, for safer therapeutic and diagnostic applications (He et al., 2023). While organic NPs are ideal for drug delivery because of their biocompatibility, they lack the tunability that metallic inorganic nanoparticles offer. Therefore, combining organic and inorganic nanoparticles into hybrid systems enhances versatility, stability, and multifunctionality (Pietersz et al., 2017). However, it is important to note that nontargeted NPs have rarely demonstrated convincing advantages that translate into clinical applications (Pietersz et al., 2017). Despite the surge in NPs research over the past decade, few NPs-based products have become commercially available.

Among metals, gold (Au) NPs are the most frequently used in biomedical applications due to their stability and low reactivity, although other metals like silver (Ag) and copper (Cu) have shown to possess promising properties (Shodeinde et al., 2020). A study found that Ag-NPs exhibit better sensing behavior than Cu-NPs across the entire infrared spectrum of the electromagnetic rays (Singh Sekhon and Verma, 2011).

Furthermore, semiconductor quantum dots (QDs) have been explored for biomedical use because of their unique optical properties. Their size, shape, and composition can be manipulated to achieve fluorescence at different wavelengths (Chan et al., 2002). Due to their much higher brightness compared to conventional organic dyes, there is significant interest in using NPs and quantum dots for biomedical imaging and biosensing. Moreover, they can be tagged to specific molecules, allowing for fluorescent detection of biomarkers (Knipe et al., 2013; Pinaud et al., 2006). Localized surface plasmon resonance (LSPR) biosensors are a promising class of sensors that confine light within metal nanostructures and measure changes in the local refractive index caused by the adsorption of target molecules (Brolo, 2012). These LSPR nano-biosensors are highly sensitive and can be easily integrated into miniaturized devices, making them ideal for point-of-care testing applications (Wang et al., 2017).

In a recent study, the authors exploited lipid-based NPs to evaluate the efficacy of encapsulated nucleic acids designed to modulate TNF-α splicing in both in vitro cell systems and in vivo murine models of colitis (Qassem et al., 2025). The encapsulated formulations were shown to be stable and well tolerated. Notably, lipid NPs preferentially accumulated in inflamed intestinal tissue at sufficient concentrations to elicit a therapeutic effect. However, the authors also observed biodistribution of these lipid NPs in other organs, suggesting the potential for off-target accumulation (Qassem et al., 2025). This finding underscores the need for improved targeting strategies to enhance tissue specificity and minimize systemic exposure. In a similar approach, IL-22 mRNA, a known for its potent anti-inflammatory and epithelial regenerative effects in ulcerative colitis was encapsulated in lipid NP and evaluated following oral administration in a murine UC model (Sung et al., 2022). Mice treated with IL-22 mRNA–loaded lipid NPs exhibited accelerated mucosal healing, as evidenced by improved body weight recovery, increased colon length, reduced histological injury scores, and decreased expression of pro-inflammatory cytokines. Collectively, these studies demonstrate that lipid-based NP serve as effective carriers for nucleic acid delivery, offering stability, safety, and therapeutic efficacy. With appropriate targeting modifications, lipid NPs hold significant potential for delivering a wide range of therapeutic cargos to specific tissues or organs in inflammatory bowel disease.

PLGA NPs have been used to encapsulate well-established anti-inflammatory therapeutics, including aminosalicylic acid and the monoclonal antibody adalimumab, both of which are commonly used in the management of IBD (Davoudi et al., 2018; Feng et al., 2025). These formulations were evaluated in vitro using cell culture and organoid systems. The studies demonstrated efficient cellular uptake of PLGA NPs and effective delivery of the encapsulated agents to inflamed cells, highlighting the potential of PLGA-based carriers for targeted drug delivery under inflammatory conditions. A similar strategy was applied in a murine colitis model, in which the Janus kinase inhibitor tofacitinib citrate—an FDA-approved therapy for ulcerative colitis—was delivered via PLGA NP encapsulation (Seegobin et al., 2025). The findings showed that approximately 80% of the drug was released in the colonic environment, and that degradation of PLGA by the colonic microbiota did not significantly alter drug release kinetics. Collectively, these results underscore the promise of PLGA NP-based delivery systems in enhancing therapeutic efficacy, enabling dose reduction, and potentially minimizing systemic side effects in IBD treatment.

Exosome-derived nanoparticles represent an emerging and promising platform for therapeutic delivery in IBD, owing to their low immunogenicity and superior tissue-targeting capabilities compared with many synthetic nanoparticle systems. In particular, plant-derived exosomes have attracted increasing interest relative to animal-derived exosomes due to their lower production costs, favorable safety profile, and generally non-toxic and non-immunogenic nature (Cai et al., 2022). In addition, plant-derived exosomes are not known to cross the placental barrier, further supporting their potential safety for clinical application (Cai et al., 2022).

Several studies have demonstrated the therapeutic potential of exosome-based delivery systems in experimental models of IBD. For example, exosomes derived from human bone marrow–derived mesenchymal stromal cells were shown to attenuate inflammatory responses and preserve intestinal barrier integrity in murine models of colitis (Liu et al., 2019). In another study, mesenchymal stem cell–derived exosomes loaded with miR-27a-3p maintained epithelial viability and barrier function in patient-derived colonoid cultures, without inducing cytotoxicity or structural disruption (Oh et al., 2025). Collectively, these findings highlight the promising application of exosome-based nanoparticles as safe and effective drug delivery vehicles for IBD therapy.

A living diagnostic system is an emerging area of research in which genetically engineered bacterial species are used to detect biological or chemical reactions within the mammalian body by producing signals proportional to the concentration of a specific analyte (Bhalla et al., 2016). Following successful proof-of-concept studies in several indications, engineered living systems are now being expanded to not only continuously monitor biological environments but also respond dynamically when and where needed. In this context, beneficial bacterial species—often probiotics—are genetically modified to develop complex, real-time sensing and therapeutic systems (Figure 4). This approach leads to the concept of a DX-RX system (Diagnose and Prescribe), also referred to as a living diagnostic-therapeutic system. The advantages of such living systems include real-time monitoring and dynamic response, targeted therapy delivery, adaptive and personalized treatment strategies, improved disease management, and reduced healthcare burden (Almekkawy et al., 2020; Alvarez-Olmos and Oberhelman, 2001; Villalobos-Quesada et al., 2023; Zhou et al., 2020). Living diagnostic-therapeutic biosensors offer a powerful and minimally invasive approach for real-time, continuous monitoring, and early detection of disease conditions. These biosensors can be ingested, worn, or implanted (Nguyen et al., 2021), enabling personalized treatment with improved accuracy and a reduced need for external intervention. Functioning as internal surveillance systems, they detect physiological changes and can deliver therapy on demand, making them promise for managing inflammatory diseases and even cancer (Bhatia et al., 2024; Hemdan et al., 2024; Howarth et al., 2005; Senf et al., 2020). Engineered with well-defined gene-regulatory networks and synthetic feedback modules, these biosensors can offer a dynamic sensing and therapeutic responses, unlike natural probiotics, which produce constant response from poorly understood systems (Landry and Tabor, 2017).

There have been significant advancements in the field of synthetic biology in recent years, and the engineering of probiotics represents the next generation of development in live biotherapeutics (Aggarwal et al., 2020). Genetically engineered probiotics can be equipped with sensing features endowed by synthetic genetic circuits specifically engineered to detect a wide range of environmental cues originating from various pathological conditions (Debnath et al., 2024). These engineered probiotics also show potential for treating difficult-to-manage conditions, including metabolic disorders, IBD, multiple sclerosis, and a range of bacterial infections (Ma et al., 2022). These systems are designed to both detect and provide therapeutic response against the underlying health conditions, functioning as part of a living diagnostic-therapeutic (DX-RX) system. Programmable probiotics offer several advantages: they are internal, provide real-time responses, are self-replicating, site-specific, non-chemical, non-invasive, and easy to administer with minimal patient preparation. They are tunable for sensitivity and are biocompatible (Garg et al., 2021; Pesce et al., 2022). For example, some probiotic biosensors are engineered to detect ROS such as hydrogen peroxide (H₂O₂) (Semwal and Gupta, 2021).

Biosensors are generally categorized into two main types: Catalytic-based biosensors, which involve enzymes, microbes, organelles, or tissues; and Affinity-based biosensors, which rely on antibodies, receptors, or nucleic acid based aptamers (Hasan et al., 2014). For the purposes of this review, we focus solely on catalytic-based biosensors.

Engineered whole cell microbes have been applied as probiotics in several formats. They have been engineered to confer unique capability to inhibit pathogens by secreting antimicrobial peptides and bacteriocins, which provide them with a growth advantage over other commensal bacterial species (Fang et al., 2018; Winter et al., 2010; Ott et al., 2004). Probiotics have been also applied to support immune regulation and may help prevent the progression of inflammatory diseases (Suez et al., 2019; Tsai et al., 2019; Shamoon et al., 2019). Lactobacilli probiotics generate various acids such as lactic, acetic, and propionic acids, that lower pH and suppress the growth of various pathogens, particularly gram-negative bacteria (De Keersmaecker et al., 2006; Shahid et al., 2017). Probiotics can therapeutically modulate the gut microbiome by degrading environmental pollutants, neutralizing microbial toxins, and alleviating disease symptoms (Romero-Luna et al., 2022; Kumar et al., 2016; Kohl et al., 2020). Advances in synthetic biology have enabled the development of engineered probiotic strains with specialized functions, including disease treatment and tumor targeting, which was impossible before (Liu et al., 2023; Chung et al., 2021; Mazhar et al., 2020).

EcN is the only well-established Gram-negative probiotic bacterium, known for being easily manipulated, transformed, and cultured, with proven safety and robust colonization potential (Scaldaferri et al., 2016; Zhang et al., 2012; Secher et al., 2017; Danino et al., 2015). Hence, EcN is one of the most extensively studied and engineered probiotic strains. EcN is the primary component of the commercial probiotic product Mutaflor, which has been used to manage various gastrointestinal disorders, including IBD, diarrhea, uncomplicated diverticular disease, and UC. In some cases, it has also contributed to digestive disease remission (Jacobi and Malfertheiner, 2011; Dembiński et al., 2016; Park, 2021). The therapeutic potential of EcN is attributed to several key characteristics: anti-inflammatory activity, support for intestinal barrier function, immuno-modulatory effects, ability to colonize and regulate the human gut microbiota, production of antimicrobial compounds, and strengthening of the epithelial barrier (Chen et al., 2023b; Han et al., 2024; Helmy et al., 2017; Hu et al., 2020; Kandasamy et al., 2016, 2017; Kumar et al., 2023; Park et al., 2021; Pradhan and Alison, 2020; Sonnenborn and Schulze, 2009; Vlasova et al., 2016). Although efforts have been made to develop probiotic biosensors, the integration of dynamically controlled genetic circuits capable of recognizing biomarkers and producing therapeutic molecules locally is still in its early stages (Liu et al., 2023). Below, we describe some of the potential engineered probiotic studies along with their outcomes. Tables 3 and 4 summarize the engineered probiotics used to treat specific GI disease conditions in both human and animal models. Given the prevalence of studies focusing on EcN, we have grouped all engineered EcN-based strains into one category, while other engineered probiotic species are presented in a separate group.

In one recent study, researchers engineered and characterized a synthetic genetic circuit in the EcN. This engineered strain was able to detect nitric oxide (NO) as a biomarker and respond by producing and secreting nanobodies that sequester TNFα, thereby reducing inflammation at the local site (Weibel et al., 2024). These findings highlight the potential of engineered probiotic as a targeted, real-time and a living biotherapeutic.

To manage IBD, researchers developed a fluorescent reporter system using E. coli by engineering fimbriae and NO-responsive regulator NorR to respond to NO an inflammatory signal. This engineered system successfully detected NO in the gut, indicating inflammation (Archer et al., 2012). A similar approach was used to detect tetrathionate, a byproduct of ROS generated during gut inflammation. In this study, researchers engineered a mouse-derived E. coli strain capable of sensing tetrathionate in the inflamed gut of mice (Riglar et al., 2017). In a separate study, EcN was engineered to overexpress catalase and superoxide dismutase for the treatment of inflammatory conditions in the gut. To enhance its stability and bioavailability in the GI tract, the engineered EcN was coated with chitosan and sodium alginate (Zhou et al., 2022). The obtained results demonstrate that this engineered coated EcN alleviated acute IBD in mice and significantly increased the abundance and richness of beneficial gut bacteria. This study provided foundational evidence that orally delivered, biofilm-coated engineered probiotics can regulate gut inflammation and relieve acute colitis in a mouse model (Zhou et al., 2022).

These studies highlight the potential of engineered bacteria as a therapeutic tool to treat and manage intestinal cancers, with the hope of future clinical translation in humans. Besides, in the above applications, engineered probiotics also have been utilized to bypass pathogen defenses through mechanisms such as anti-quorum sensing, anti-biofilm activity, antibiotic production, quorum sensing modulation, and signal interference (Salman et al., 2023; Vestby et al., 2020; Gao et al., 2019; Rizzello et al., 2014).

Chronic inflammatory disorders of the gastrointestinal tract are increasing globally, driven in part by changes in lifestyle, dietary patterns, and environmental exposures, resulting in a rapidly evolving disease epidemiology. Current diagnostic approaches remain limited in their ability to provide real-time, longitudinal assessment of disease activity, while existing therapeutic strategies largely rely on long-term systemic administration of anti-inflammatory or immunosuppressive agents, often accompanied by significant adverse effects. Emerging technologies, including NP-based diagnostic and therapeutic platforms, offer promising opportunities to address several limitations of conventional approaches by enabling targeted delivery and enhanced disease-site specificity. In parallel, living diagnostic–therapeutic systems based on whole-cell sensors represent an innovative strategy for real-time detection and on-demand intervention in chronic inflammatory conditions, although still in their infancy, early preclinical and limited clinical studies have demonstrated encouraging potential. Nevertheless, both NP-based and living therapeutic approaches face substantial challenges related to safety, scalability, regulatory approval, and clinical translation. With growing interdisciplinary interest and continued efforts to address these barriers, the coming decade of research is likely to play a critical role in shaping the successful integration of these emerging technologies into real-world clinical practice.