Immunomodulatory biomaterials for treating chronic inflammation at mucosal sites

Engineering immunomodulatory biomaterials for chronic inflammation at mucosal tissue sites relies on overcoming both fundamental challenges associated with mucosal barrier function and the unique immune microenvironment of mucosae during inflammatory processes. Given the expansiveness of this field and its accelerating progress, we will focus on two select tissues, the lungs and the gastrointestinal tract, and we will not seek to provide a comprehensive cataloging of all recent research. Rather, we will highlight selected vignettes from the past few years that demonstrate specific evolving concepts. First, a brief section will orient the reader to the main biological processes that are sought to be controlled and regulated; following this, select examples of recent progress in this dynamic research area will be highlighted. More comprehensive discussions of mucosal biomaterial vaccines can be found in other recent reviews^1,2.

Inflammation after tissue injury is a multifactorial process with a reparative timeline following three distinct stages associated with the activity of specific immune cell subsets. Although different inflammatory diseases associated with mucosal tissues have unique pathologies, they also share generalities (Fig. 1). In the early pro-inflammatory stage, an initial response is commonly mounted in response to damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) from damaged cells or pathogens, respectively. For example, resident immune cells, including neutrophils and tissue-specific macrophages, are commonly activated and release inflammatory mediators that recruit CD4 + T helper1 (T_H1) cells and circulating monocytes to aid in pathogen clearance and angiogenesis. In the second stage, as the inflammatory cytokine milieu begins to subside, a reparative phenotype is commonly induced with the recruitment of regulatory T (Treg) cells, T_H2 cells, and M2-like macrophages responsible for producing pro-regenerative cytokines, including TGF-β and IL-10^3,4.

The final resolution stage involves an active host response to restore tissue integrity. The clearance of pro-inflammatory mediators results in an overall decline in the number of infiltrating immune cells at the tissue injury site, which in turn prompts pro-regenerative cells to restore homeostatic tissue conditions^5,6. Dysregulation of this overall repair timeline results in an extended chronic inflammatory state, which contributes to deterioration of immune tolerance, tissue injury, or a fibrotic pathology^7,8,9.

At mucosal tissue sites, the progression of chronic inflammation is further characterized by additional processes that reflect pathological changes to its unique tissue architecture (Fig. 1). Mucosal tissues line various body cavities and organs exposed to the external environment and include the oral cavity, respiratory, gastrointestinal, and genitourinary tracts. The mucosa consists of three layers, including an epithelial surface layer consisting of either simple columnar or stratified squamous cells, an underlying lamina propria containing specialized mucosal-associated lymphoid tissue (MALT), and a deeper layer of smooth muscle. Goblet cells in the epithelial layer secrete mucus, which traps foreign particles and pathogens, preventing their entry into deeper tissues¹⁰. In studies with Muc2-deficient mice unable to secrete a functional mucus layer, gut dysbiosis triggered the early onset and perpetuation of colitis as invading pathogens could more easily proliferate, breach the epithelial layer, and recruit local lymphocytes¹¹.

In addition to this protective mucus layer, mucosal tissue responses following an insult are unique because of the immune properties inherent to their epithelial cells. Some gut-specific specialized immune cells include goblet cells containing “antigen passages” which traffic antigens in the lumen to dendritic cells in the underlying lamina propria¹², intestinal epithelial cells capable of phagocytosis of commensal fungi¹³, and tuft cells which secrete IL-25 in response to parasitic infection¹⁴. When both cellular barriers and the immune response of these specialized cells fail, microbial dysbiosis can be yet another initiator of chronic inflammation. For example, in a study where the microbiota from inflammatory bowel disease (IBD) patients were transplanted into germ-free mice, naïve T cells were differentiated towards a T_H17 state, resulting in the perpetuation of colitis pathology¹⁵. Furthermore, T_H1-mediated inflammation following intestinal colonization by specific strains of pathogenic bacteria has also been demonstrated to also induce IBD in genetically-susceptible mice models^16,17.

Regardless of the type of insult, one of the most obvious tissue architecture changes that is a hallmark of unresolved chronic inflammation is the development of tertiary lymphoid organs (TLOs) at the mucosal tissue sites. Mature TLOs are ectopic lymphocyte clusters that share similarities with secondary lymphoid organs as they contain organized T-cell zones, B-cell follicles, and high endothelial venules¹⁸. The formation of TLOs is primarily driven by cytokine-mediated activation of resident stromal cells, such as fibroblasts, endothelial cells, and smooth muscle cells. These activated cells produce homeostatic lymphoid chemokines that recruit and retain leukocytes at the site of inflammation. Depending on the disease context and timeline, TLOs can either benefit or burden disease resolution. For example, in the case of T_H2-mediated acute allergic inflammation, it was observed in mice that the presence of iBALT did not worsen allergic responses to repeated pulmonary allergen exposure. Instead, these mice had reduced T_H2 cytokine mRNA expression, eosinophil recruitment, and mucus production. The authors of this study hypothesize that the iBALT structures created a local concentration of immune cells that were responsible for sequestering effector T cells and antigens in a manner that minimizes widespread tissue inflammation¹⁹. Whereas TLOs in these acute conditions regress with the return to tissue homeostasis, in chronic inflammatory diseases, extended exposure to stimuli leads to continued recruitment and activation of immune cells, including dendritic cells and follicular helper T cells, responsible for promoting B cell activity and structural maturation of TLOs. For example, in studies conducted with lung samples derived from patients with chronic obstructive pulmonary disease (COPD), iBALT formation correlated with disease severity as elevated levels of chemokines CXCL12, CXCL13, and cholesterol metabolites facilitated CD4 + T cells secretion of the cytokines IL-6, IL-1β, and TGF-β and the polarization into T-follicular helper cells by type 2 dendritic cells²⁰. The authors of this study suggest that the persistence of these immune cell subsets in the context of this disease results in a self-amplifying positive feedback loop that promotes the persistence of the iBALT structure and exacerbations of the chronic inflammatory state²⁰. In more severe cases, TLOs even induce tissue damage as exemplified in lung biopsies of rheumatoid arthritis patients with pulmonary complications. Trichrome and α-SMA+ staining of these biopsies revealed collagen deposition near iBALT germinal centers, suggesting a pathological consequence of such dysregulated local immune activity²¹. Considering the dynamic role TLOs play in disease resolution, targeting key cellular or chemokine drivers of these ectopic structures offers a unique therapeutic target to either engage or curtail this localized immune machinery, depending on the type and exposure of a given insult.

Another distinguishing feature of mucosal tissue sites is the active downregulation of immune responses to innocuous antigens, as is the case with certain airborne particulates in the respiratory tract and food antigens or commensal bacteria in the digestive tract. In healthy physiologic states, the preferential immune-tolerant state is maintained by both the innate and adaptive immune system, with the existence of tolerance-inducing innate effector cells such as dendritic cells and the broadly neutralizing activity of mucosal secretory IgA antibodies, respectively. For example, in the mesenteric lymph nodes, specialized CD103+ dendritic cells exposed to innocuous oral antigens produce retinoic acid, which, in synergy with TGF-β, supports the differentiation of naïve T cells into Foxp3+ Treg cells, helping to establish local immune tolerance in the gut²². Furthermore, in a seminal study conducted by Murai and collaborators, the role of IL-10 secretion by local CD11b + CD11c+ dendritic cells in the gut was also elucidated as pivotal in maintaining Foxp3 expression of Tregs in the context of colitis prevention²³. Following an insult, mucosa-specific Tregs have also been shown to play an essential role in maintaining homeostasis by preventing hyperactivity of a type 2 immune response^24,25,27. In a study conducted with mice deficient in peripheral Tregs, it was demonstrated that a loss of this cell population resulted in upregulation of IL-4 and IL-13, loss of commensal bacteria, and intestinal epithelial pathology, including colonic crypt hyperplasia upon microbial exposure²⁴.

In the most severe cases, mucosal tissue sites that enter this state of type-2 specific immune dysregulation experience an excessive accumulation of extracellular matrix (ECM) components deposited by myofibroblasts, resulting in tissue fibrosis^26,27. In vivo studies with lung fibroblast samples from idiopathic pulmonary fibrosis (IPF) patients revealed that IL-13 significantly promotes the expression of α-SMA and collagen I by upregulating the expression of TGF-β, in contrast to fibroblasts derived from healthy patients²⁸. Furthermore, oxidative stress prompted by recruited innate immune cells and local pulmonary fibroblasts further contributes to fibroblast activation through the activity of NADPH oxidase (NOX) derived reactive oxygen species (ROS). Studies have demonstrated that by engaging in a positive feedback loop with TGF-β, ROS concentrations in the tissue amplify further, promoting cytokine-induced fibroblast-myofibroblast transition and fibrosis²⁹. The imbalance between the new ECM production by these activated fibroblasts and degradation by matrix metalloprotease enzymes results in increased matrix stiffness and scar tissue formation, compromising normal tissue architecture and function³⁰.

The design of immunomodulatory biomaterials to treat chronic inflammation at these mucosal sites must strike a fine balance between promoting therapeutic activity by polarizing immune cells towards a more regulated response while simultaneously minimizing any detrimental interactions between the biomaterial itself and the mucosal barrier. While there are other reviews that discuss the role of biomaterials to treat chronic inflammation broadly^9,31,32,33, this perspective piece will particularly highlight novel biomaterial designs that address these challenges in two central mucosal tissue sites in the body: the respiratory and digestive tracts.

One of the key innate immune cell types that can drive the fibrotic state are macrophages. Although at one time distinguished as either “classically” activated M1 macrophages or “alternatively activated” M2 macrophages, recent advancements in single-cell RNA sequencing have demonstrated the plasticity of this cell type in phenotypic expression in response to environmental cues^37,38. With this in mind, macrophage heterogeneity can be better described as existing on a spectrum or a “multidimensional network of states,” where factors including tissue context, stimuli, and function can correlate back to cell marker expression³⁸. This understanding of macrophage heterogeneity helps biomaterial researchers identify disease-specific macrophage phenotypes for targeting, and it recognizes that the function of macrophages is highly dependent on the state of the tissues in which they persist.

In the lungs, tissue-resident alveolar and interstitial macrophages are responsible for maintaining tissue homeostasis, but in chronic inflammatory conditions such as IPF, monocyte-derived alveolar macrophages (Mo-AMs) upregulate the secretion of pro-fibrotic cytokines, resulting in aberrant fibroblast proliferation and ECM deposition. Recent studies have demonstrated that there exists an “immune-stromal” crosstalk that further accelerates the transition from favorable acute repair to destructive chronic fibrosis^39,40. Work done by Hinz and collaborators has elucidated key adhesion protein interactions via cadherin-11 that facilitate specific macrophage-fibroblast binding interaction, which prompts TGF-β activity and consequently differentiation of profibrotic myofibroblasts⁴⁰. This research demonstrates the importance of considering the downstream myofibroblast activity of the tissue stroma when designing biomaterials that specifically target macrophage polarization for fibrosis resolution.

In a study published by Singh et al., researchers (Fig. 2) consider this crosstalk when developing an IPF therapeutic using mannosylated albumin nanoparticles designed to target the mannose receptor CD206, which is up-regulated in Mo-AMs. In their experiment, intravenously administered nanoparticles delivering a TGF-β-siRNA payload were preferentially internalized by Mo-AMs in the lung that were actively expressing the TGF-β cytokine⁴¹. Five days after bleomycin-induced fibrosis, the nanoparticles significantly reduced cytokine levels of pro-fibrotic TGF-β and IL-1β in lung tissue homogenates, which correlated with decreased disease severity as observed in lung histology and functional tests. The authors attribute this mitigation of fibrosis to reduced pathologic crosstalk between the M2-like macrophages and proximal fibrogenic fibroblasts⁴¹. A similar macrophage-targeting strategy was also demonstrated to be advantageous by Ghebremedhin and collaborators in a bleomycin-induced pulmonary fibrosis mouse model⁴². Subcutaneous delivery of a host-defense-derived peptide targeting CD206+ cells three days following bleomycin administration, led to selective modulation of the M2-like Mo-AMs. Specifically, RP-832c induced repolarization of the M2-like macrophages to the M1 phenotype (as described by a shift to bacterial phagocytic activity)⁴³ or triggered apoptosis in the CD206+ macrophage population. This resulted in a reduction of downstream pro-regenerative cytokines, which consequently reduced myofibroblast activity and ECM deposition while improving lung structure. These observations correspond to previous studies that demonstrated the specific role infiltrating monocytes play in responding to TGF-β and the ability to mitigate the fibroblast dysregulation if this population of macrophages is reduced⁴².

Both studies discussed here illustrate mitigation of fibrosis progression at lung mucosal sites using technologies that rely on reducing infiltration of circulating monocytes to diminish pathologic crosstalk between polarized macrophage populations and fibroblasts. To expand upon the findings illustrated by both papers, it would be interesting to develop biomaterials that not only are target-specific (CD206+ monocyte-macrophages) but also stimuli-responsive. In the case of diseases like IPF, where a positive-feedback loop exists between dysregulated cytokines and the ECM, acute exacerbations of the disease are a concern^44,45. Developing a biomaterial, that confers immune memory for exacerbations of fibrotic conditions can prevent the need for multiple administrations of a therapeutic and provide a crutch for maintaining long-term tissue homeostasis.

Broadening the utility of immunomodulatory biomaterials requires delivery strategies where targets can be reached with precision to stringently control the immune phenotype. Current therapeutic options to treat pulmonary chronic inflammation in the case of IPF or following infections such as SARS-CoV-2 primarily fall short when trying to cross mucosal tissue barriers and engage local immune cells. Thus, engineering biomaterials such that they are amenable to local delivery routes to access the lower respiratory tract and raise effective mucosal immune responses are an important research area in biomaterial design. Molecules delivered via an aerosol route can achieve up to 100 times higher concentrations within the lung compared to the oral route of delivery⁴⁶. This, in turn, makes aerosolized therapeutics more capable of engaging local APCs such as dendritic cells and alveolar macrophages⁴⁷.

Application of an inhalable therapy for treating chronic inflammatory diseases in the lungs was recently demonstrated by the Cheng group with the delivery of lung spheroid cell secretomes and exosomes to promote lung repair in pulmonary fibrosis⁴⁸. Delivery of these cell-based therapies into the respiratory space had a significant influence on modulating the lung immune microenvironment while also restoring tissue architecture and function in both bleomycin and silica models of pulmonary fibrosis in mice. Cytokine analysis of mouse serum from the secretome and exosome treatment groups indicated a downregulation of monocyte-chemoattractant protein 1 (MCP-1), which has previously been reported to play a role in lung inflammation⁴⁹. Proteomic analyses used to elucidate the molecular mechanisms of the secretome-mediated repair pathway indicated an overall downregulation in the expression of the myofibroblast marker α-SMA and the pro-inflammatory cytokine IL-4, while MMP-2 activity was upregulated⁴⁸. The authors of this paper attribute this to the role select matrix metalloprotease enzymes play in late-stage fibrosis tissue repair, thus highlighting the connection between ECM proteins and anti-inflammatory mediators during the resolution stage of chronic inflammation.

Building on this foundational exosome work in the context of pulmonary diseases, Wang and collaborators recently demonstrated the effectiveness of inhaled biomaterials and therapeutics for infectious disease applications with a consideration towards preemptively reducing chronic inflammation-associated tissue fibrosis. In their 2022 paper, the researchers designed RBD-Exo VLP, a virus-like particle (VLP) utilizing exosomes as a delivery vehicle for the SARS-CoV-2 receptor-binding domain (RBD)⁵⁰. Inhalation delivery of this exosome-based VLP vaccine offered significant advantages in increasing antigen availability to lung-resident APCs and consequently promoting mucosal antibody and T-cell responses. In comparison to their liposome controls, the authors hypothesized that the exosome-derived VLPs had better distribution within the lung parenchyma and APC internalization because of shared surface proteins and membrane features. When administered directly to the respiratory tract via nebulization, the VLPs stimulated the production of antigen-specific IgA antibodies in the airways and tissue, even in the absence of adjuvant. Furthermore, the inhaled VLPs also enhanced T_H1-biased cellular responses, which were significant in promoting viral clearance while reducing potential vaccine-associated airway restructuring or fibrosis. This was reflected in their in vivo study when the researchers challenged hamsters with high-dose SARS-CoV-2 following administrations of the RBD-Exo VLP vaccine. Histological data revealed a reduction of fibrotic pulmonary lesions in the treatment groups in comparison to the PBS control groups, which also corroborated the protective antibody titers measured. Additionally, neutrophil myeloperoxidase (MPO)-positive cells were reduced in the lungs of the RBD-Exo treatment group, reflecting a controlled inflammatory involvement, as previous literature has indicated the role of neutrophil hyperactivity as an agent of aberrant ECM turnover and lung fibroblast proliferation^50,51. Taken together, this study highlights the role that local delivery plays in raising mucosal immunity to provide both immediate and durable protection in the case of SARS-CoV-2 and similar respiratory infections that can lead to long-term chronic inflammation if left untreated⁵⁰.

Both articles described in this section highlight the advantage local delivery provides in preventing the development of fibrosis, whether initiated by an infectious disease or progression of a chronic inflammatory state. However, an important consideration to be made with the introduction of therapeutic biomaterials directly into the lungs is the development of iBALT structures. While both papers addressed changes in tissue architecture, closer inspection of the type and organization of recruited myeloid and lymphoid cells can provide information regarding the repair timeline and the role biomaterials can play in restoring tissue homeostasis. With this information, biomaterial therapeutics can be tailored to either 1) take advantage of iBALT formation to quickly eliminate foreign insults capable of inducing chronic inflammation or 2) suppress iBALT persistence to prevent responses against self-antigens and downstream tissue modifications that result in poor functional outputs.

Dysregulated, chronic inflammatory responses at the intestinal mucosal site can lead to the development of long-term health consequences, including intestinal bowel disease, fibrosis, and gastrointestinal cancer^52,53, emphasizing the need to engineer next-generation therapies to mitigate chronic inflammation within the intestines. Clinical manifestations of chronic intestinal inflammation include ulcerative colitis (UC) and Crohn’s disease (CD), together referred to as IBD. While IBD etiology is multifactorial and complex, there is a common understanding that IBD development can be traced to dysregulated mucosal immune responses to the gut microbiome and autologous tissue in response to environmental triggers in patients with genetic predisposition⁵⁴. In the United States alone, IBD is estimated to impact between 2.4 and 3.1 million people, and its prevalence is expected to continue to increase^55,56. The current treatment landscape includes first-line amino-salicylates (5-ASA), corticosteroids, methotrexate, and thiopurine immunomodulators for moderate cases of IBD, and Janus kinase (JAK) inhibitors and biologics against a variety of inflammatory cytokines and integrins for severe cases of IBD⁵⁷. For patients with moderate-to-severe IBD, prolonged reliance on biologics can result in infections and a loss in treatment responsiveness due to targeting of dominant cytokines or generation of anti-drug antibodies (ADAs) against the infused mAbs^58,59. Anti-TNF monoclonal antibodies infliximab and adalimumab, for example, had a 60.0% and 68.4% loss of response by year three, respectively, associated with a 44.0% and 20.3% incidence of ADAs, respectively⁶⁰. These and other shortcomings of current treatments and the increasing prevalence of IBD motivate further development of innovative strategies to combat chronic intestinal inflammation.

The effective delivery of therapeutic agents to the site of intestinal inflammation is difficult, considering the various barriers, including drastic changes in pH, the presence of lytic enzymes, and dense layers of polysaccharide mucus. Because of the delivery challenges, many biomaterial strategies within this therapeutic area focus on delivering small molecule immunosuppressants via micro- and nanoscale delivery systems, which have been comprehensively reviewed by others^61,62. This perspective section instead focuses on biomaterials that are directly immunomodulatory and successfully reprogram the inflammatory state within the gastrointestinal tract.

Gut homeostasis is mediated primarily by the mucosal epithelium and mucus barrier, commensal bacteria, and the resident immune cells⁶³. The epithelial cells and mucus layer physically shield the underlying tissue, while resident immune cells facilitate tolerance towards healthy, commensal bacteria and food antigens. Disruption in gut homeostasis can result in an inappropriate innate immune response to intestinal bacteria, leading to aberrant adaptive inflammation and tissue damage seen in intestinal chronic inflammatory diseases⁶⁴. Innate immune cells, including dendritic cells, macrophages, and neutrophils, release pro-inflammatory cytokines and chemokines, resulting in cell migration and infiltration into the intestinal tissue. Circulating neutrophils, monocytes, and lymphocytes interact with tissue integrin ligands on the surface of vessels and extravasate into the tissue, where they secrete inflammatory molecules, further contributing to the inflammatory cascade within the intestines⁶⁵. Cellular infiltration into the intestinal tissue is a hallmark of IBD and has been clinically validated as a target for reducing pathogenic inflammation. Patients with IBD tend to overexpress gut-tropic integrins and cell adhesion molecules within inflamed intestinal tissue, compared to their healthy counterparts, directly leading to enhanced cell infiltration and inflammation within the intestines⁶⁶. Various anti-integrin monoclonal antibody therapeutics, including natalizumab, vedolizumab, and ontamalimab, have been designed to block interactions between cell adhesion molecules and leukocytes to prevent excess cell infiltration into the intestinal tissue. While these mAbs demonstrate therapeutic efficacy in some patient groups, primary and secondary non-response rates remain hurdles; for example, in a recent clinical trial of ontamalimab, 52.7% of originally responding patients experienced relapse⁶⁷.

Motivated by the unmet need for strategies to address chronic intestinal inflammation in CD, researchers at Northwestern University have developed an approach to reduce cellular infiltration in the intestines utilizing lipid-conjugated peptide sequences derived from uteroglobin protein. This study was a collaborative effort between researchers working in the urologic, gastrointestinal, and vascular regeneration space, led by Arun Sharma and Samuel Stupp, aimed at designing a platform to efficiently deliver, protect, and present a bioactive peptide sequence in the inflammatory milieu of the small intestine. Their engineered peptide amphiphiles self-assemble into supramolecular nanofiber structures with high aspect ratios and allow for high-density display of the bioactive peptides⁶⁸. The peptide sequences, called antiflammins (AFs), have demonstrated pleiotropic, anti-inflammatory properties, including the ability to reduce leukocyte adhesion, accumulation, and function in inflamed tissue via reduced adhesion molecule expression (Fig. 3)^69,70. When injected directly into lesions in a murine model of ileitis, anti-inflammatory peptide amphiphiles (AIF-PAs) led to a significant decrease in the expression of adhesion/trafficking molecules CD62L (L-selectin) and CD18 and decreased infiltration of CD68+ macrophages/mononuclear phagocytes, CD4+ lymphocytes, CD11c+ myeloid-derived cells, and MCT+ mast cells. Further, the treatment led to reductions in pro-inflammatory cytokines and an increase in pro-regenerative cytokine concentration within the lamina propria. Unexpectedly, AIF-PAs also led to a re-polarization of lesion-associated macrophages towards an M2-like, CD206 + , pro-regenerative phenotype, encouraging the authors to apply these assemblies to murine models of urethroplasty, where they observed inflammation resolution and angiogenesis⁷¹. Altogether, the researchers leveraged antiflammin peptide nanofibers (AIF-PAs) to reduce pathogenic inflammation and reprogrammed the mucosal immune response towards a pro-regenerative state. These findings further support the notion that modulating the expression of cell adhesion molecules and integrins can be used to mitigate gastrointestinal inflammation. and that antiflammin-based biomaterial structures may be useful for accomplishing this.

While this strategy is innovative in concept and application, it relies on direct injection into the intestinal lesions, which may limit systemic immunomodulation and may be specifically beneficial for patients with severe CD where surgery is required to resect damaged tissue. As highlighted in the article, the authors acknowledge this as a major shortcoming and briefly discuss further materials engineering to optimize the formulation for oral delivery, including decorating the AIF-PAs with polyethylene glycol (PEG) and increasing bioactive peptide density. Further, like many studies regarding biomaterials, a larger emphasis should be placed on more extensive immune profiling, including more specificity regarding lesion-infiltrating immune cells and their respective expression markers following treatment. This has been recently highlighted in a comment published in Nature Reviews Bioengineering by Doloff and colleagues⁷²; and we echo their call for more well-rounded immune profiling. Overall, however, the collaborative work from Northwestern University moves the needle for the use of peptide-based biomaterials for modulation of chronic intestinal inflammation via adhesion molecule expression and resulting immune infiltration.

ROS are oxygen-containing molecules with unpaired electrons, which make them highly unstable and reactive. ROS are normally produced during metabolism and are rapidly scavenged via intracellular antioxidant systems, preventing excess ROS and oxidative stress-induced damage to cellular structures. In a healthy system, intestinal cells produce low levels of ROS to regulate gut microbes and maintain immunological homeostasis. While the pathogenesis of IBD is complex and multifactorial, overproduction of ROS is a hallmark of chronic intestinal inflammation⁷³. The inability to scavenge excess ROS results in mucosal tissue damage, leading to an influx of microbes from the intestinal lumen and infiltration of immune cells in response, further contributing to a positive feedback loop of pathogenic inflammation.

Because of its role in inflammation and increased prevalence in intestinal mucosal tissues during chronic inflammation, many drug delivery strategies and therapeutic modalities have been engineered to respond to and neutralize ROS. Numerous delivery systems have been designed to allow for ROS-responsive release of therapeutic drugs, which are further detailed in previous reviews^74,75. Instead, we will focus on a particular biomaterial strategy that directly neutralizes ROS to reduce pathogenic inflammation.

Motivated by the unmet need for strategies to address intestinal inflammation in IBD, researchers have developed an approach to reduce ROS-mediated damage in the intestines using biomaterial conjugate amphiphiles (Fig. 3)⁷⁶. This work was conducted by Lee, Moon, and colleagues, with the goal of creating an immunomodulatory platform that allows for local delivery to inflamed tissues. Their engineered nanomedicine conjugates self-assemble into particles, hyaluronic acid-bilirubin nanomedicine (HABN), with a bilirubin core and a hyaluronic acid (HA) shell, leveraging the immunomodulatory effects of both components in their formulation.

Bilirubin has demonstrated immunomodulatory effects, primarily through direct ROS-scavenging properties, but also through intranuclear regulation of transcription factor Nrf2, increasing the expression of heme oxygenase (HO-1) and antioxidants^77,78. HA, a glycosaminoglycan found in the synovial fluid and ECM, has also demonstrated various immunomodulatory effects, including the ability to regulate macrophage activation⁷⁹, antimicrobial peptide expression in intestinal epithelial cells⁸⁰, and Treg cells⁸¹, all of which contribute to a beneficial immune response and intestinal healing. While both HA and BR have been previously found to be immunomodulatory, their clinical development has been hampered due to various delivery challenges, including enzyme-mediated HA turnover and BR solubility issues; when formulated into HA-BR conjugates, both HA turnover and BR solubility were overcome. Motivated by the various delivery challenges associated with intestinal inflammation, the researchers aimed to create a platform that was both immunomodulatory and could achieve targeted intestinal delivery by creating HA-BR amphiphile conjugates (HABNs).

The HABN formulation demonstrated ROS scavenging and cytoprotective properties in vitro, encouraging further studies in an in vivo model of colitis. When administered via oral lavage, the researchers found that the platform preferentially accumulated within damaged intestinal tissues and impacted the inflammatory state of the tissue. HABN treatment specifically increased expression of tight-junction proteins and improved barrier function, decreased MPO activity and ROS-induced apoptosis within the epithelium, and altered the cytokine profile towards pro-regenerative, anti-inflammatory cytokines IL-10 and TGF-β. Interestingly, HABN treatment also impacted the gut microbiome, increasing bacterial richness, diversity, and the abundance of beneficial bacterial species.

The novel strategy outlined by Lee et al. outperformed conventional treatment regimens in a murine model of DSS-induced colitis, including 5-aminosalicyclic acid (5-ASA), methylprednisolone (MPS), and dexamethasone (DEX), in full bodyweight recovery, maintaining colon length, and reducing colonic damage and MPO activity, highlighting the potential clinical impact and encouraging further development. More recently, Lee has continued developing the HABN nanoparticle platform and has since applied the ROS-scavenging system to other disease contexts, including cancer and liver fibrosis, in more recent work^82,83,84.

The biomaterial design and delivery strategy employed by Lee, Moon, and colleagues, and the resulting efficacy data, further exemplify the importance of biomaterial immunomodulation and local delivery for reducing mucosal inflammation. The preferential uptake of material by damaged tissue likely reduces potential off-target effects, and the resulting local reduction in ROS activity was efficacious in an acute murine model of DSS-induced colitis. Moving forward, evaluation in a chronic model of DSS-induced colitis may determine the durability of immunomodulation, long-term implications following ROS reduction, and efficacy in a more clinically relevant model. Additionally, as mentioned in the previous vignette, more rigorous immune profiling could elucidate the HABN’s impact on immune cell polarization, activation, and effector functions within the colonic epithelium; macrophages are key inflammatory mediators in colitis and therefore would be interesting to investigate further. Altogether, the shift towards biomaterials being used as both delivery platforms and immunomodulatory agents, like the HABN nanoparticles discussed, promises to expand opportunities to develop therapeutics for other chronic inflammatory diseases in the future.

As previously described, chronic inflammatory disorders in mucosal tissues are multifactorial and arise from complex interactions between the mucosa and immune cells, motivating the development of multi-pronged approaches or the targeting of upstream molecules, such as cytokines, that play a pivotal role in orchestrating the pathogenic immune response. Analogous approaches are currently used in the clinic, where many patients turn towards passive immunotherapy biologics if their disease becomes refractory to steroids immunosuppressants⁸⁵. These monoclonal antibodies generally target inflammatory mediators, including cytokines (TNF, IL-12, and IL-23) and extracellular proteins (such as integrins), to reduce and block inflammation within the tissue following systemic infusion. While this is therapeutically beneficial to some, monoclonal antibodies come with their own set of challenges, including high primary and secondary non-response rates, required long-term patient compliance with repeated infusions, and high costs.

Active immunotherapies have historically been used to vaccinate patients against foreign infection-causing agents, such as bacteria and parasites, with great success⁸⁶. In more recent years, active immunotherapies have been explored for applications in inflammatory disorders. These active immunotherapies can achieve a reduction in inflammation by stimulating the patient’s own immune system to raise humoral and cellular responses against a given self- or non-self-inflammatory antigen, typically with more durable responses, limiting the need for frequent, repeated monoclonal antibody injections^87,88. Active immunotherapies have been developed to raise humoral responses against a variety of inflammatory targets, including cytokines, pathogens, and angiogenic factors, all of which are relevant to the pathogenesis and sustained inflammation seen in both the lungs and gastrointestinal tract. Researchers have demonstrated improved disease outcomes in murine models of IBD with therapeutic or prophylactic administration, highlighting their potential for future pre-clinical development⁸⁸. Because active immunotherapies engage the patient’s immune system and do not rely on delivering monoclonal antibodies parenterally, there is an opportunity to exploit alternative delivery routes for increased local efficacy, decreased systemic exposure, and ease of use.

Combining these trends, our group has engineered biomaterials that generate immune responses to inflammatory targets and delivered these materials directly to mucosal tissues to resolve local inflammation. We have investigated the targeting of multiple different cytokines in various disease contexts, including TNF⁸⁹, IL-17⁹⁰, complement anaphylatoxins^91,92,93, IL-1β,⁹⁴, and natural antibody epitopes such as phosphorylcholine (PC)^95,96. These approaches can be divided into two categories of strategies. In the first, we have investigated ways to reproduce the therapeutic effect of passively administered biologics (i.e., monoclonal antibodies), but by inducing the generation of the antibodies continuously rather than injecting them periodically. Such an approach may have advantages over conventional monoclonal antibody treatment by avoiding the generation of ADAs that lead to the loss of therapeutic efficacy. In the second approach, we are seeking to engage auto-reactive antibody processes that already exist within humans: natural antibodies. Natural antibodies are prevalent in the human antibody repertoire, are commonly autoreactive, and serve myriad functions, including regulation of vascular wall homeostasis, clearance of apoptotic debris, and rapid response to conserved microbial epitopes⁹⁷. One of the most well-characterized natural antibody epitopes is PC, which is exposed on the surface of apoptotic cells, oxidized lipids, and on some bacterial cell walls. Our interest in PC-reactive natural antibodies stems from their recognized function in clearing damaged tissue and restoring homeostasis⁹⁸, which we hypothesized could be induced using carefully designed immunogens. Peptide nanofibers bearing highly multivalent PC epitopes stimulated significant anti-PC antibody responses, which were efficacious in both therapeutic and protective models of colitis⁹⁵. Peptide assemblies are an attractive platform for immunogen design because they themselves are minimally inflammatory, capable of raising durable antibody responses with no adjuvant or minimal adjuvant^99,100. Further, when PC-nanofibers were delivered orally, they mounted gastrointestinal and systemic humoral responses against PC, which led to improved intestinal barrier function, reduced disease severity, and reduced colon shortening in a murine model of DSS-induced colitis⁹⁶. The assemblies were both stable within the GI tract and immunogenic, demonstrated by the generation of local antibody responses. We believe that this approach of engaging endogenous processes for regulating inflammation by designing immunogens capable of stimulating protective or therapeutic antibody responses holds significant promise as an alternative to current treatments based on biologics or monoclonal antibodies.

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Authors and Affiliations

1. Department of Biomedical Engineering, Duke University, Durham, NC, USA

   Lauren M. Babb, Maria J. Kulapurathazhe & Joel H. Collier

Contributions

L.M.B., M.J.K., and J.H.C. wrote the manuscript.

Corresponding author

Correspondence to Joel H. Collier.

Competing interests

J.H.C. is listed as an inventor on multiple patents and patent applications relating to active immunotherapies based on peptide assemblies.

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