Nanotechnology-Based Modulation of Autoimmune Microenvironments in Sjögren’s Syndrome: A Review of Mechanistic Perspectives

Introduction

The Sjogren’s syndrome (SS), now being more commonly referred to as Sjögren’s Disease (SjD), can be defined as an autoimmune disease wherein there exists an autoimmune attack on the exocrine glands, particularly the salivary and lacrimal glands, causing problems like dry mouth syndrome (xerostomia) and dry eyes syndrome (keratoconjunctivitis sicca).¹ This disease is now considered as a prototype for autoimmune epithelitis wherein there is significant involvement of the epithelial cells in triggering the immune system response.² Apart from the glandular presentation, SS has systemic involvement of other organs such as lungs, kidneys, nervous system, and vascular structures, highlighting its systemic autoimmune nature.³ SS develops via complex mechanisms, involving interactions between innate and adaptive immune systems, which include the activation of the type I interferon (IFN) signaling pathway, B cell hyperactivity, and the production of autoantibodies. Inflammation leads to slow destruction of glands and tissues.⁴ Notably, the formation of lymphocytic infiltrates consisting of large numbers of CD4⁺ T-cells and B cells in the salivary glands represents the importance of the local immune microenvironment in the pathogenesis of the disease.²

The condition predominantly affects women, particularly those in their middle age, owing to various hormonal and genetic factors.⁵ It may be considered one of the most common forms of systemic autoimmune diseases, but the prevalence rate will be affected by geographical factors and classification.^6,7 The symptoms of Sjogren’s syndrome are not limited to the sicca syndrome but involve such conditions as fatigue, arthralgia, neuropathies, as well as involvement of the organs of the body.⁸ It is also noteworthy that SS patients have a higher incidence of lymphoproliferative disorders, especially B-cell non-Hodgkin’s lymphomas, which result in morbidity and mortality.⁹ Moreover, the disease is associated with high economic cost as a result of long-term management of the disease, late diagnosis, and the absence of any cure for the disease. It has been revealed by various studies that the symptoms of the disease are variable.¹⁰

SS may be co-occurrent with other systemic or organ-specific autoimmune diseases such as systemic lupus erythematosus (SLE) or neuromyelitis optica spectrum disorder /neuromyelitis optica (NMOSD/NMO). The clinical relevance of these overlapping syndromes is possibly due to the similar immunologic mechanisms such as the activation of type 1 interferon, B cell hyperactivity, production of autoantibodies, imbalance of the cytokines and inflammatory damage in target tissues. In this context the nanotechnology driven approaches that allow for the targeted modulation of immune responses, controlled delivery of anti inflammatory agents, redox modulation or the antigen specific immune tolerance might be helpful for the treatment of not only for SS but also for other overlapping syndromes.^11,12 However, this is a theoretical event and further research is required to see if manipulation of common auto-immune pathways via nanomedicine platforms can be safe and effective in patients with overlapping SS, SLE, and NMOSD/NMO.

In spite of all the recent developments in understanding the pathophysiology of SS, treatment has remained focused on symptomatic measures, which are largely ineffective. Conventional therapy is focused on alleviating the symptoms of dryness and lowering systemic inflammation with the help of immunosuppressive drugs and biological agents. However, conventional treatment techniques might fail to bring about disease reduction.¹³ Biological treatments, particularly for B-cells, including anti-CD20 and B-cell activating factor (BAFF) inhibitors, have shown erratic results among patients of Sjogren’s syndrome because of the varied immune system processes that lead to this disorder.^14,15 Moreover, systemic immunosuppressant drugs have been known to possess severe side effects, alongside a lack of effectiveness, since they are not able to selectively affect the inflamed glands.^13,15 These limitations suggest the necessity of developing more focused therapies targeting specific pathways involved in modulating the immune response locally, rather than suppressing the immune system at large.³

It is thought that the role of the autoimmune microenvironment constitutes a key characteristic of the onset and progression of SS. The term autoimmune microenvironment refers to a sophisticated environment made up of various cells and substances in tissues where chronic inflammation occurs.² The local microenvironment plays a role in maintaining continuous activation, survival, and differentiation of immune cells, which in turn results in maintaining signaling pathways of inflammation leading to disease development and tissue damage.¹⁶

It has been shown recently that epigenetic modulation through DNA methylation, histone modifications, and noncoding RNAs contributes significantly to the immune response in SS microenvironments, leading to dysregulated gene expression and inflammation in the salivary glands.^17,18 The epigenetic mechanisms act as a dynamic interface between environmental signals and immune dysfunction, sustaining abnormal immune response.^18,19 Thus, approaches that concentrate on modifying the autoimmune environment rather than targeting particular immune mechanisms have been considered as possible therapeutic interventions to maintain the balance of the immune system.²

Breakthrough for immunotherapy treatment due to the development of nanotechnology, which provides the opportunity to have control over the immune system response.²⁰ Delivery of therapeutics to sites of inflammation or to particular immune cells may be accomplished by the use of engineered nanoparticles. This will improve effectiveness of the treatments while lowering their toxicity.²¹ Nano systems have demonstrated remarkable potential as an approach to induce tolerance against specific antigens, manipulate cytokine profiles, and modulate immune cell functions in autoimmune diseases, which is a revolution in the field of immunology.²² As for SS, recent studies show that nanotechnology could possibly help solve many problems connected with conventional treatment by means of altering the disease microenvironment. For example, there has been some study on the role played by extracellular vesicles and nanotechnology in regulating the body’s immune system and promoting wound healing.²³ This implies the enormous capacity of nanotechnology in developing precision immunomodulation treatments for autoimmune disorders.

The purpose of this paper is to provide an overall evaluation of nanotechnology-based strategies that allow for the reprogramming of immune microenvironments in SS. While conventional techniques focus on suppressing the effects of systemic immunity, this study highlights the role of localized immune microenvironments in the progression of the disease and its resistance to treatment. The research examines how the advances in immunology, nanomedicine, and systems biology can be combined to develop innovative ways to manipulate immunity, restore immune tolerance, and regenerate glands. One of the biggest drawbacks within the current body of evidence is that the nanotechnology-based strategies have not been directly tested in patients with Sjögren’s disease or directly tested in disease-specific Sjögren’s animal models. Thus, their importance to Sjögren’s disease is mainly speculative and mechanistic. The potential of nanomedicine platforms to safely and effectively target these pathways in the pathogenesis of Sjögren’s is not certain and these pathways are likely to be targeted in Sjögren’s disease. Going forward, validation into appropriate Sjögren’s disease models, pharmacokinetic, biodistribution, toxicity, immunogenicity and efficacy studies should be performed prior to clinical translation.

Methodology

This is a narrative review, which was created using a literature search in PubMed, Scopus, Web of Science and Google Scholar. Searches were conducted with the combinations of keywords: “Sjögren’s syndrome”, “Sjögren disease”, “autoimmune microenvironment”, “nanotechnology”, “nanomedicine”, “nanoparticles”, “drug delivery”, “immunomodulation”, “B-cell activation”, “interferon signaling”, “BAFF”, “cytokines”, “oxidative stress”, “epithelial dysfunction”, “ectopic lymphoid structures” and “precision medicine”. Peer-reviewed articles were searched primarily from 2015 to 2026 (and prior pioneering articles) with a focus on recent studies, as well as foundational literature relevant to the pathogenesis of SS. As direct clinical study of nanotechnology based therapy in patients with SS is limited or lacking, the studies discussed in this review were chosen based on mechanism of relevance rather than disease-specific clinical validation. We focused our investigations on nanoplatforms targeting immune and tissue-injury pathways that are thought to play a role in SS pathogenesis and that include interferon-associated inflammation, B-cell activation, cytokine signaling, oxidative stress, epithelial function, antigen presentation, lymphoid organization and regenerative repair. These studies thus need to be understood as being preclinical or conceptual in nature, and support future investigation in SS, not as proof of therapeutic efficacy in SS. Articles were excluded if they did not include a mechanism or a translational perspective relevant to the scope of this review, if they were not related to autoimmune pathogenesis, or if they were not relevant to the modulation of immune/tissue microenvironment by nanotechnology.

Pathophysiology of Sjögren’s Syndrome

Genetic and Environmental Triggers

The etiopathogenesis of SS is a result of the complex interaction between genetic and environmental influences. Through genome-wide association studies, loci within the HLA class II region and non-HLA gene clusters like IRF5 and STAT4, which play an important role in regulating the interferon pathway and immune function, were found to be associated with SS.¹⁹ The environmental triggers, especially viral infections, have been proposed to trigger disease onset through the activation of innate immunity pathways and production of type I interferon, which serves as a key driver for autoimmunity.²⁴ These components, when put together, create an environment that is conducive to dysregulated immunity and chronic inflammation.

Role of Epithelial Cells in Disease Initiation

The assurance of SS is that the epithelial cell activation is part of the immune response pathway. This supports the idea of autoimmunepithelitis. The salivary gland epithelial cells are non-professional APCs presenting MHC molecules and providing co-stimulatory signals to activate the T cells.² Moreover, these cells secrete chemokines and cytokines that attract immune cells and maintain the inflammatory response. Apoptosis of epithelial cells results in the secretion of intracellular autoantigens, which further activate the immune response and promote loss of tolerance.²⁵ This interplay between the epithelium and immune system creates a cycle of inflammation that feeds on itself, which is vital in the pathogenesis of the disease.

Autoantibody Production (Anti-Ro/SSA, Anti-La/SSB)

The development of autoantibodies is another major characteristic of SS because of the abnormal regulation of B cells. The development of these antibodies occurs in response to the performance of the autoantigen after the exposure of cellular antigens due to epithelial cell apoptosis.²⁶ Immune complexes formed in this manner can lead to the activation of the complement system and inflammation. It should be noted that the formation of autoantibodies may occur even before any signs appear, which emphasizes their diagnostic significance.⁶

Lymphocytic Infiltration and Germinal Center Formation

Lymphocyte infiltration of the exocrine glands is one of the most common features of SS pathogenesis. The infiltrating lymphocytes include CD4⁺ T cells and B cells that form germinal center-like lymphoid aggregates. Such lymphoid aggregates provide conditions for antigen presentation, B cell differentiation, and somatic hypermutation and thus support autoantibody production.⁴ Such persistence of well-organized immunological tissues reveals disease severity and a tendency towards lymphoma formation. Chronic lymphocyte infiltration causes glandular degeneration and subsequent loss of function. Other chronic auto-immune conditions such as inflamed synovial tissue in rheumatoid arthritis and CNS associated auto-immune inflammation in multiple sclerosis/CNS auto-immunity have also been reported to display similar tissue associated lymphoid aggregates or tertiary lymphoid structures. Thus, lymphoid aggregate formation in SS must be understood in the context of the chronic tissue-specific autoimmunity in which persistent antigenic stimulation and local immune organization might be expected to be important in the amplification of disease activity and the maintenance of autoreactive B and T-cell responses.^27,28

Cytokine Networks

Cytokine imbalance plays an important role in the etiology of SS, and type I interferons have been identified as being crucial to the disease. They help in antigen presentation, activate B-cells, and increase inflammation.²⁶ Contemporarily, BAFF is an important regulator of B-cell survival and differentiation; thus, autoantibodies are produced in response to it. Cytokines that exhibit pro-inflammatory activity, such as IL-6 and TNF-α, also lead to immune stimulation and destruction. Moreover, cytokines such as IL-21 connect innate and adaptive immunity through T follicular helper cell and B-cell activation processes.²⁹ Interactions between these cytokines generate an inflammatory network that sustains the development of diseases.

B-Cell Hyperactivity and T-Cell Dysregulation

One of the key characteristics of SS is the hyperactivation of B-cells that proliferate, differentiate to plasma cells, and produce excessive amounts of immunoglobulins due to factors such as cytokines like BAFF and T follicular helper cells.^24,30,31 Moreover, the dysfunction of T-cells is caused by the imbalance between effectors and regulatory cells. Th1 and Th17 contribute to inflammatory responses, whereas regulatory T-cells lose their suppressor activity, resulting in immune tolerance disruption. A feedback loop formed between B and T cells in the autoimmune environment ensures the persistence of inflammation and cell damage.^4,32–37

Autoimmune Microenvironment in Sjögren’s Syndrome

Definition of Autoimmune Microenvironment

SS autoimmune microenvironment describes a very specific and dynamic milieu in affected exocrine glands, specifically salivary glands, where immune cells, epithelial structures, stromal components, and soluble factors collaborate in order to perpetuate the ongoing process of chronic inflammation. This microenvironment is described by constant state of immune system activation, dysfunctional cytokines signaling, and remodeling, all leading to malfunctioning of the affected glands. In contrast to systemic immune responses, the microenvironment is defined as a perpetual source of inflammation that controls the process of immune cell recruitment, differentiation, and proliferation. Recent studies have identified increased activity of specific pathways involved in antigen presentation, lymphocyte activation, and interferon response in SS salivary gland tissues. The overall immune microenvironment organization of salivary gland is shown in Figure 1.³⁸

Figure 1 Ectopic lymphoid structures (ELSs) formed within the salivary glands of a patient with Sjögren’s syndrome. The central component consists of ectopic germinal centers (EGCs), which are organized into dark and light zones. In the light zone, germinal center B (GcB) cells are selected by follicular dendritic cells (FDCs). Non-selected GcB cells undergo apoptosis, whereas positively selected cells differentiate into memory B cells or plasma cells under the influence of follicular helper T (Tfh) cells, or are eliminated via Tfh-mediated regulation. In parallel, T peripheral helper (Tph) cells produce IL-21 and CXCL13, promoting B cell activation; memory B cells further differentiate into plasma cells under the combined influence of BAFF and related survival factors. Plasma cells accumulate around ductal and acinar epithelial cells expressing CXCL12, contributing to local autoantibody production. Distinct B cell–rich and T cell–rich zones are present surrounding the EGCs. High endothelial venules (HEVs) develop in the T cell–dominant areas at the periphery of lymphoid aggregates, a process driven in part by CCL21 secreted from myofibroblast-like stromal cells. Inflammatory stimulation, including viral triggers, induces IFN-γ expression, which promotes CXCL9 and CXCL10 release, facilitating further recruitment of circulating T and B lymphocytes into the gland via HEVs and sustaining chronic information.38

Immune Cell Composition

SS autoimmunity microenvironment is made up of a combination of innate and adaptive immunity cells that synergize in the process of disease pathogenesis. The immune cells’ interactions play a crucial role in setting the level of inflammation through their interplay.

T Helper Subsets (Th1, Th17, Tfh)

CD4⁺ T helper (Th) cells play an important role in coordinating the response to autoimmune disease in SS. Th1 cells generate interferon-γ, which leads to macrophage activation and inflammation, while Th17 cells secrete IL-17, leading to chronic inflammation and epithelial damage. T follicular helper cells (Tfh) are especially important for their role in activating B cells and producing antibodies. These cell types are abundant within the salivary gland infiltrate, helping to organize immune structures.³⁹ The difference between these T cell populations establishes an inflammatory milieu that contributes to the chronic nature of the disease.

Regulatory T Cells (Tregs)

The regulatory T cells (Tregs) play a vital role in ensuring immune tolerance; however, the functioning of the Tregs is compromised in SS. While Tregs can be found in the sites of inflammation, their ability to suppress the activity of other immune cells may be hampered by alterations in signaling mechanisms and exposure to inflammatory cytokines. This compromise results in an inability to regulate autoimmunity, leading to chronic inflammation. The involvement of Tregs in disrupting immune tolerance is evident in the context of SS.⁴⁰

B Cells and Plasma Cells

B cells play an important role in SS pathogenesis and are a prominent feature of the autoimmune milieu. B cells become activated and expand their clone into plasma cells, producing autoantibodies responsible for disease pathology. Glandular milieu promotes the survival and maturation of B cells due to the effect of cytokines like BAFF. This abnormal activity of B cells is accompanied by immune complex formation, inflammation, and the development of lymphoma. It has been shown in numerous studies that autoreactive B lymphocytes are crucial in the development of SS.^3,30,41,42

Dendritic Cells and Macrophages

The role of innate immune cells like dendritic cells (DCs) and macrophages is very important for contributing to the SS microenvironment. The plasmacytoid DCs generate large quantities of type I interferons that enhance immune response and facilitate adaptive immunity.^43–46 On the other hand, the macrophages are involved in damaging the tissue by generating pro-inflammatory cytokines and reactive oxygen species. Innate immune cells are thus involved in linking the environment with adaptive immunity.³⁸

Stromal and Epithelial Cell Interactions

Both epithelial and stromal cells are involved in contributing to the autoimmune microenvironment in SS. The salivary gland epithelial cells serve as non-professional antigen-presenting cells, while releasing cytokines like CXCL13 and CCL21 that facilitate the recruitment and accumulation of the lymphocytes. In addition, the role played by the stromal cells is to provide a framework that helps in retention and organization of the immune cells. The interaction of the epithelial and the immune cells generates a feedback mechanism, which ensures the development of inflammation and remodeling of the tissues.²

Hypoxia, Oxidative Stress, and Metabolic Reprogramming

The autoimmune microenvironment of SS consists of hypoxia and oxidative stress that play an important role in modulating immune responses. The hypoxic environment created by the inflamed glands triggers the activity of hypoxia inducible pathways resulting in inflammation and increased immune cell viability.^47,48 On the other hand, the increase in reactive oxygen species (ROS) levels causes epithelial destruction and promotes immune responses. Research in recent times has also shown that metabolic changes, such as glycolysis, are responsible for the activation of immune cells and the expression of their effector functions.³⁸

Ectopic Lymphoid Structures (ELS)

Ectopic lymphoid structures (ELS) are characteristic features of the SS microenvironment that mimic the secondary lymphoid organs in their anatomy and physiology. ELS possess organized B cell follicles, T cell areas, and FDC networks, which make it possible to present antigens locally and undergo affinity maturation.^49,50 The development of ELS is mediated by chemokines and cytokines that control lymphocyte trafficking and localization. ELS are linked with greater disease severity and the propensity for lymphoma due to their ability to induce B-cell activation and antibody production.³⁹

Immune Checkpoint Dysregulation

Immune checkpoints are vital players in regulating the immune system. These checkpoints play a key role in balancing immune activation while promoting immune tolerance. Disruption in the immune checkpoints, including Pd-1 and CTLA-4, results in an inability to inhibit immune activation and causes overactivation of autoreactive T-cells in SS. The development of immunotherapy through the inhibition of immune checkpoints can be considered a promising new approach in treating SS.¹⁰

Therapeutic Targets Within the Autoimmune Microenvironment

In SS, the autoimmune microenvironment is a sophisticated, ever-changing milieu comprising various immune cells, epithelial compartments, and soluble factors that maintain ongoing inflammation. Treatment targeting the autoimmune microenvironment can be considered a novel therapy, as this approach provides opportunities to modulate local immune dysfunction without suppressing the entire immune system. Studies have highlighted the need for therapies to interrupt abnormal signaling networks, re-establish immune homeostasis, and correct metabolic defects in the target glandular niche.³⁸

Cytokine Modulation

Cytokine-mediated signaling is vital for generating an SS microenvironment, especially BAFF and type I IFN signaling. BAFF is essential for inducing B cell survival, maturation, and autoantibody formation, causing continuous B cell activation. Increased BAFF expression in salivary glands maintains autoreactive B cell clones, leading to disease advancement.³⁸ The interferon pathway, particularly the type I interferons, is the primary upstream mediator that activates the immune system in SS. IFN signaling facilitates antigen presentation, induces B-cell activation, and amplifies cytokine feedback loops. Significantly, transcriptomics studies have revealed IFN gene expression as an important biomarker of disease severity and treatment efficacy.⁵¹ Consequently, IFN pathway modulation via receptor blocking or signaling inhibition is becoming an attractive strategy with increasing proof of its efficacy as a critical target for treating SS.⁵²

Immune Cell Reprogramming

Immune cell reprogramming is a paradigm change that moves from traditional immunosuppressive approaches to more precise immunomodulatory techniques. In SS, immune response is generated due to aberrant interactions between T cells, B cells, and innate immune cells. Immune cell reprogramming entails altering their functional behavior and phenotype to correct any immune imbalance.^2,53 For instance, manipulating Th subsets, specifically T follicular helper (Tfh) cells, decreases B-cell activity and autoantibody generation. Furthermore, modifying macrophages’ phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) reduces inflammation and enhances the process of inflammation resolution. Additionally, dendritic cells are vital targets since altering their antigen presentation capability inhibits T-cell proliferation and cytokine secretion.^36,38 Nanoparticle-based targeted delivery of the drug is one such strategy that allows selective targeting of particular types of immune cells, reducing toxicity to the whole body. Such a treatment paradigm matches the idea of microenvironment remodeling by changing the functional state of immune cells in tumor tissue.^54–56

Inhibition of Ectopic Germinal Centers

The presence of ectopic germinal centers (GCs) or lymphoid organs is crucial for creating a proper SS microenvironment and represents the local place of antigen presentation and B cell maturation to autoantibody-producing plasma cells. Ectopic lymphoid organs support persistent immune response and represent a significant marker of severe SS and lymphoma occurrence.^57,58 The approach to targeting the ectopic GC involves the inhibition of the mechanisms involved in ectopic GC formation and maturation. Lymphotoxin, chemokine CXCL13, and follicular dendritic cells are critical for ectopic GC maintenance, and interfering with these mechanisms may result in impairment of lymphoid organogenesis and immune response in the region.³⁸ In addition, manipulating Tfh cells, which regulate the functions of the GCs, can inhibit B cell activation and the development of autoantibodies. It is also possible to decrease the presence of auto-reactive immune responses by breaking down these complex immune niches.^45,59,60

Restoration of Immune Tolerance

One of the critical problems associated with SS involves the disruption of immune tolerance, resulting in the stimulation of autoreactive lymphocytes. Thus, the restoration of immune tolerance has become an essential treatment strategy. Interventions designed to increase the potency of Tregs or induce antigen-specific tolerance have been extensively investigated.^61,62 Tregs are crucial for immune tolerance regulation; however, their immunosuppressive effect may be compromised in SS. By enhancing Treg functions, patients suffering from SS can achieve better suppression of autoimmunity and decrease inflammatory processes. Moreover, tolerogenic dendritic cells may be modified to deliver antigens in a non-inflammatory setting, thus inducing immune tolerance.⁶³ Novel therapies include antigen-specific tolerance induction utilizing modern delivery systems, such as nanoparticles. These techniques facilitate selective exposure of self-antigens to the immune system, minimizing immunosuppression without compromising the immune response. Significantly, this method addresses the root cause of the immune malfunction rather than just managing the disease manifestations.^22,64,65

Targeting Oxidative Stress and Hypoxia

Oxidative stress and hypoxia are two major characteristics of the SS environment and contribute immensely to disease progression. Increased oxidative stress results from high amounts of ROS that lead to cellular damage, release of autoantigens, and inflammation. Hypoxia, on the other hand, increases inflammation through hypoxia-inducible factors (HIFs) that regulate gene expression for survival and cytokines in immune cells.³⁸ The treatment options based on such metabolic alterations consist of antioxidants, ROS scavengers, and blockers of hypoxia-induced signaling pathways. Such strategies seek to interrupt the feedback mechanism of oxidative stress and activation of the immune system.^4,66,67 It is worth highlighting that due to recent developments in nanotechnology, stimuli-responsive systems have been created that release drugs in oxidative or hypoxic conditions. This allows achieving an efficient effect while avoiding adverse consequences.^68–71

Nanotechnology in Autoimmune Disease Management

Nanotechnology provided an innovative approach towards autoimmune diseases based on technologies for manipulating immunity, optimizing pharmacokinetics, and achieving targeted delivery of therapeutic interventions. For example, in the case of an autoimmune disease like SS, where there is constant activation of the immune system along with an increase in immune cell populations in the salivary and lacrimal glands, the regulation of medicines to suppress the immune system showed limited efficiency in achieving remission in the disease condition. The introduction of nanotechnology has provided an innovative solution for addressing such problems by programming the immune response and reinstating immune tolerance.⁷²

Overview of Nanomedicine Platforms

The different nanomedicine platforms that have been utilized in autoimmunity treatment therapies are lipid-based nanocarriers, polymeric nanoparticles, dendrimers, metallic nanoparticles, and biomimetic vesicles. Among lipid-based nanocarriers are LNPs like liposomes and solid lipid nanoparticles, which are utilized because of their high biocompatibility, as well as the capacity to encapsulate both hydrophilic and hydrophobic drugs.⁷³ The PLGA nanoparticle, on the other hand, allows sustained release, while dendrimers provide multivalency for ligand conjugation.^74,75 According to recent studies, lipid-based nano-carriers play a pivotal role in optimizing pharmacokinetic properties and delivering therapies in autoimmune disorders. Lipid-based nanoparticles such as liposomes, nano-structured lipid carriers, and lipid micelles have been found to optimize therapeutic performance in preclinical autoimmune models.⁷⁶ Moreover, biomimetic nanocarriers that mimic natural cell membranes are becoming more popular due to their potential to improve immune compatibility and increase circulating times, thus providing high suitability for treating chronic autoimmune disorders.⁷⁷

Advantages of Nanotechnology in Immunomodulation

One of the main benefits of using nanotechnology in autoimmune disease treatment is the potential for exact immunomodulation without the need for complete immunosuppression. Traditional treatments like steroids and disease-modifying antirheumatic drugs (DMARDs) inhibit the general immune response and leave patients vulnerable to infections. However, nanoparticles make it possible to selectively target specific harmful immune cell populations, such as autoreactive B cells, activated T cells, and inflammatory macrophages.⁷⁸ Nanoparticles can be designed to deliver therapeutic agents such as cytokine inhibitors, small interfering RNA (siRNA), and antigen-specific peptides specifically to immune cells. With this approach, it is possible to regulate the pathways involved in immune response such as nuclear factor-kappa B (NF-κB), Janus kinase-signal transducer and activator of transcription (JAK/STAT), and inflammasomes. Moreover, nanomaterial-based therapy can induce a shift in macrophage phenotype from inflammatory M1 to anti-inflammatory M2 types.⁷²

Targeted Drug Delivery Mechanisms

Specific drug targeting can be done by passive and active methods. Passive drug targeting is carried out based on inflammation-related increased permeability and retention of the nanoparticles in inflamed tissues.⁷⁹ In contrast, active drug targeting uses the coating of nanoparticles with certain biomolecules such as antibodies, peptides, and ligands to facilitate receptor binding.⁸⁰ Autoimmune disorders like SS result in the activation of endothelial cells to produce adhesion molecules like ICAM-1 and VCAM-1. Also, in autoimmunity, the use of nanoparticles coated with antibodies specific to CD20 (B cells) and CD4 (T helper cells) allow selective destruction of abnormal lymphocytes. It has been shown that specific targeting of monocytes/macrophages with nanoparticles is important for controlling inflammatory environments and immune activation.⁸¹ Exosome-mediated mechanisms, diagnostics, and treatment in pSS is shown in Figure 2.⁸²

Figure 2 (A) Exosomes from EBV-infected B cells and activated T cells impair salivary gland epithelial function by delivering miRNAs that disrupt calcium and cAMP signaling, reducing AQP5 expression and saliva secretion. (B) Salivary, serum, and tear exosomes contain diagnostic biomarkers (eg, Ro/SSA, La/SSB, circRNAs) for non-invasive detection and disease monitoring in pSS. (C) MSC-derived exosomes modulate immune balance (Treg/Th17), promote tissue repair, and restore salivary gland function, offering a potential therapeutic strategy.82 Abbreviations: pSS, primary Sjögren’s syndrome; EBV, Epstein–Barr virus; AQP5, aquaporin 5; STIM1, stromal interaction molecule 1; SERCA2B, sarco/endoplasmic reticulum Ca2⁺ ATPase 2B; RyR2, ryanodine receptor 2; Ro/SSA, Sjögren’s syndrome-related antigen A; La/SSB, Sjögren’s syndrome-related antigen B; miRNA, microRNA; MSCs, mesenchymal stem cells; iPSC-MSCs, induced pluripotent stem cell-derived MSCs; UCMSCs, umbilical cord MSCs; DPSCs, dental pulp stem cells; OE-MSCs, olfactory ecto-MSCs; SHEDs, stem cells from human exfoliated deciduous teeth; MDSCs, myeloid-derived suppressor cells; MSCs-exos, MSC-derived exosomes).

Controlled Release and Stimuli-Responsive Systems

Controlled release technologies constitute an important innovation in autoimmune treatments using nanotechnology. They can deliver their cargo based on certain pathological stimuli, such as low pH, high levels of ROS, enzymes, or cytokines.^83,84 The inflamed milieu of autoimmune disease is characterized by oxidative stress and changes in enzymes, making it possible to use these conditions as stimuli for targeted drug delivery. Nanoparticles that respond to ROS have been synthesized for delivering anti-inflammatory drugs to the inflamed salivary gland without affecting other tissues. Additionally, MMP-responsive nanocarriers degrade due to the increased levels of matrix metalloproteinases (MMPs). The application of biomaterials engineering techniques in addition to these techniques makes drug delivery even more precise. The stimuli responsive nanomaterials give control over the amount of drugs released into the system, maintaining high drug levels in the disease site while decreasing the toxicity of the drugs.⁸⁵

Safety and Biocompatibility Considerations

Despite their therapeutic potential, nanomedicine platforms need to be critically evaluated concerning safety, toxicity, and biocompatibility. The toxicity of nanoparticles can be associated with their physicochemical characteristics such as particle size, charge, surface modification, and their degradation products. In this regard, cationic nanoparticles might cause membrane damage and oxidative stress in case of improper design.^86,87 Degradable polymers like PLGA, lipids, and natural nanoparticles obtained from extracellular vesicles are regarded as safe because they metabolize easily and have less immunogenic effects. Moreover, modifications such as PEGylation improve biocompatibility by minimizing the process of opsonization and increasing circulation time. On the other hand, prolonged accumulation and elimination pathways need to be examined in preclinical animal models.⁸⁸ Recently published articles have underscored the significance of standardizing toxicity assessment methodologies such as biodistribution, immune response profiling, and target organ accumulation.⁸⁹ Furthermore, the issue of regulatory importance still remains critical to the translational aspect of medicine, especially in making sure that the therapeutic effect is reproducible and scalable.

Nanotechnology-Based Strategies for Reprogramming Autoimmune Microenvironments

The reprogramming of the autoimmune microenvironment of SS necessitates an integrated approach to immune regulation that focuses on the modulation of cytokines, activation of autoreactive lymphocytes, oxidative stress imbalance, hypoxic reprogramming, and disruption of epithelial-immune interactions. The microenvironment of SS in the salivary and lacrimal glands involves chronic lymphoid infiltration, activation of type I interferon signaling, and germinal centers.^2,4,90 Nanotechnology presents a sophisticated therapy approach that is able to influence these pathologic mechanisms via targeted delivery techniques, reprogramming immune cells, and responsive release mechanisms of drugs. Current research highlights the ability of nanomaterials to serve not only as vectors but also as activators of the immune system, facilitating a transition from immunosuppressive to immune normalization.

Nanoparticle-Mediated Cytokine Regulation

Cytokine imbalance plays a vital role in microenvironment dysregulation within the context of autoimmunity, especially an increase in TNF-α, IL-6, BAFF, and Type 1 Interferons, leading to B cell hyperactivity and chronic inflammation.⁹¹ Regulation of cytokines using nanoparticles makes it possible to inhibit inflammatory signaling pathways, such as NF-κB and JAK/STAT, without inducing generalized immunosuppression. Several studies on lipid and polymer-based nanoparticles have been conducted in the past for siRNA and mRNA delivery to knock down transcription of pro-inflammatory cytokines.^92,93 Recently, there have been developments in nanoparticle gene delivery technology emphasizing their capabilities in regulating cytokine response in immune cells along with improved pharmacokinetics and intracellular delivery.⁹¹ These delivery systems minimize overproduction of cytokines by directly administering nucleic acids to macrophages and dendritic cells, hence balancing the immune system in the inflamed tissue.

Nanocarriers for Immune Cell Targeting

The use of nanocarrier technology allows for highly targeted delivery to specific immune cells associated with autoimmune disease such as T cells, B cells, macrophages, and dendritic cells.

T-Cell Modulation

T-cell dysregulation, especially an increase in Th1 and Th17 cell subtypes, is known to be one of the prominent immunopathological features of Sjogren’s syndrome. The up-regulation of T helper cells that secrete IL-17 and follicular helper T cells has been observed in patients, being highly correlated with disease progression and the development of autoantibodies.³⁶ Additional studies have shown that abnormal activation of CD4⁺ T cells in SS leads to stimulation of B cells and systemic immune dysfunction, making T cells an important treatment focus.⁹⁴ Nanoparticles engineered to deliver immunomodulators to specific subsets of T cells using antibodies or ligands that specifically target CD4⁺ and CD8⁺ T cells have been made possible through nanoparticle engineering. This enables selective delivery of immunosuppressive drugs such as calcineurin inhibitors, mTOR inhibitors like rapamycin, and JAK inhibitors directly into activated lymphocytes with minimal toxicity.⁹⁵ The ability of biomaterial systems to work with advanced technology has shown that surface-engineered nanoparticles can be made to specifically bind with the circulating T cells to control the immune response in a tissue-specific manner.⁵⁴ From a functional standpoint, these nanocarriers inhibit the effector T cell activation pathways such as TCR-based signaling and cytokine production, while at the same time promoting the proliferation of Treg cells.²² Cationic nanoparticles have displayed great potential for eliciting immune tolerance by altering the mechanisms of antigen presentation and T cell activation processes.⁹⁶

B-Cell Depletion Strategies

The role played by B cells in the development of SS involves the generation of autoantibodies, the presentation of antigens, and the development of ectopic germinal centers. Some B-cell targeting approaches based on nanoparticles involve the use of CD20-functionalized particles and BAFF inhibitors.^95,97–99 By regulating monocyte and macrophage activation in nanomedicine treatment, indirect effects on B cells can be achieved via reduction of inflammatory cytokines produced in autoimmune niches, thus interfering with pathogenic feedback loops.⁸¹

Nanoparticles for Antigen-Specific Immune Tolerance

Induction of antigen-specific tolerance is a revolutionary concept in the treatment of autoimmunity. Nanoparticles may be constructed to deliver both the disease-linked autoantigen along with immunosuppressive cytokines such as IL-10 and rapamycin, facilitating tolerogenic DC development and regulatory T cells.^64,100,101 The proposed approach is able to suppress autoimmunity in patients while maintaining the overall functionality of the immune system. Cationic and polymeric nanoparticles have been found capable of reprogramming the immune response towards tolerance by increasing antigen presentation through inflammation-free mechanisms.⁹⁶

ROS-Responsive and Redox-Modulating Nanoplatforms

Oxidative stress is an important cause of cell injury in SS, characterized by the excessive production of ROS, which damages the epithelium and enhances inflammatory responses. ROS-sensitive nanoparticles are engineered to deliver drugs only when the environment is oxidative.^102,103 The nanocarriers utilize ROS-sensitive linkages, such as thioketal bonds, that allow for specific drug delivery. Furthermore, ROS-sensing nanoparticles can effectively remove ROS molecules from cells, restoring redox homeostasis and preventing downstream NF-κB signaling.^104–106 They have been demonstrated to enhance therapeutic efficacy in inflammatory disorders by concurrently lowering oxidative stress and inflammation.^107,108

Hypoxia-Modulating Nanomaterials

Autoimmune tissues affected by chronic inflammation often exhibit a state of hypoxia due to the presence of hypoxia inducible factor-1α (HIF-1α). Hypoxia contributes to autoimmune disorders by causing fibrosis, production of pro-inflammatory cytokines, development of new blood vessels, and alteration of cellular metabolism.^47,109,110 Nanoparticles that can be used to deliver or generate oxygen can reverse hypoxic status and inflammatory environments. Nanoparticles based on perfluorocarbons contain oxygen in significant amounts and have been widely studied as oxygen delivery agents aimed at overcoming hypoxia and blocking hypoxic signaling. Concurrently, nanoparticles loaded with catalase convert hydrogen peroxide into oxygen and suppress HIF-1α.^111–113 Also, catalytic nanozymes that display both catalase-like and superoxide dismutase-like properties are capable of regulating ROS production, maintaining optimal oxygen balance, and preventing immune-related inflammation. Oxygen-regulating nanoparticles are thus capable of restoring metabolic balance inside the tissue and constitute potential therapies for the treatment of autoimmune disorders such as SS, rheumatoid arthritis, and systemic lupus erythematosus.^110,114,115

Exosome-Mimicking Nanovesicles

The exosomes mimicking nanovesicles can be regarded as the biomimetic advance of nanomedicine, which is intended to mimic the structure and functions of EVs found naturally. The nanocarriers facilitate efficient communication between cells and modulate immunity via delivery of proteins, lipids, messenger RNA, and miRNA to recipient cells.^116,117 Exosome-like nanoparticles engineered to carry anti-inflammatory miRNAs or cytokines can promote the polarization of macrophages toward anti-inflammatory phenotypes, reducing inflammation in tissues within autoimmune microenvironments.^118,119 They benefit from the advantage of better biocompatibility, prolonged circulation time, and reduced immunogenicity as compared to other artificial nanocarriers, which makes them ideal candidates for treating chronic autoimmune diseases requiring lifelong treatment.^116,120 Furthermore, vesicles derived from exosomes are involved in cell-to-cell interaction within immune cells, as well as controlling inflammatory signal transduction pathways by means of exosomal ncRNAs and miRNA interactions.^121,122 It should be noted that there is currently a great deal of research being done on the role of engineered exosomes in regulating the immune system and providing therapeutic options in autoimmune diseases.¹²³ Exosome-mimicking nanovesicles have emerged as promising biomimetic delivery systems due to their intrinsic biocompatibility, immune regulatory capacity, and ability to transport bioactive molecules in SS (Figure 3).¹²⁴

Figure 3 Exosomes as biomarkers and therapeutic tools in Sjögren’s syndrome.124

Emerging Mechanisms in Sjögren’s Syndrome Pathogenesis and Nanotechnology-Based Therapeutic Opportunities

In addition to classical immune mechanisms like interferon activation, BAFF-mediated B-cell stimulation, T-cell dysregulation and ectopic lymphoid organisation, several new mechanisms are now emerging and are discussed with regard to SS pathogenesis. These involve ferroptosis, immunometabolic remodeling, mitochondrial dysfunction, cellular senescence, endoplasmic reticulum (ER) stress, defective autophagy and cell-type-specific disease programs uncovered by single-cell transcriptomic analysis. All these processes might contribute to understanding why glandular epithelial cells are not just passive targets of inflammatory processes, but can be active participants in local activation.^125,126

Iron-dependent lipid peroxidation-associated cell death called ferroptosis may be a driver of epithelial injury and oxidative tissue damage. Immunometabolic dysregulation may lead to changes in function of epithelial cells, macrophages, B cells and T cells, including changes in energy utilization, cytokine production and survival pathways. This mitochondrial dysfunction can increase ROS production, innate immune activation and epithelial stress signaling. Defective autophagy, ER stress and senescence-associated secretory factors could play a role in sustaining inflammation and impairing protein handling, antigen processing, epithelial homeostasis, and immune tolerance, which would be a consequence of cellular senescence.^127,128

All of these mechanisms provide new targets for nanotechnology-based intervention. Such strategies may involve antioxidant or anti-ferroptotic nanoparticles for decreasing lipid peroxidation, mitochondria-targeted nanocarriers for decreasing mitochondrial stress, metabolic modulators using controlled release systems, nanoplatforms to regulate autophagy or ER-stress pathways, and local delivery systems to decrease senescence-associated inflammatory signaling. Single-cell transcriptomic profiling could also provide additional precision in nanomedicine by identifying epithelial, immune, stromal and endothelial cells most associated with disease activity and therapeutic resistance. These strategies however are still preliminary and their validity for SS needs to be confirmed in patient-derived organoids, in disease-specific animal models and in well designed translational studies.^129,130

Representative Nanoplatforms Studied in Sjögren’s Syndrome

The use of nanotechnology-based therapeutic systems for treating various autoimmune diseases, including SS, is now regarded as an effective strategy owing to its potential advantages in targeted and controlled drug delivery, modulation of immunity, tissue specificity, and reduced systemic toxicity. Traditional drugs like corticosteroids, hydroxychloroquine, and immunosuppressive drugs used for treating SS suffer from low efficiency and a host of side effects following prolonged treatment. The pathological environment of SS involves several biological components such as infiltration of lymphocytes into salivary and lacrimal glands, oxidative stress, programmed cell death of epithelial cells, and secretion of pro-inflammatory cytokines. Hence, the current research efforts concentrate on creating nanomaterials that are able to deliver immunosuppressive drugs locally, retain themselves in the eye and salivary gland region, and bring about restoration of normal immune function. Furthermore, nano-materials can perform additional functions, including antioxidants, mimicking of immune reactions, and sustained release of therapeutic agents, which are useful in chronic autoimmune diseases.^131,132

Polymeric Nanoparticles for Immunosuppressive Drug Delivery

Polymer nanoparticles represent one of the most extensively studied nanocarrier systems for the treatment of autoimmune diseases due to their good biocompatibility, degradation properties, and efficient drug loading capacity. The focus of utilizing polymeric nanoparticles in SS has been on delivery of corticosteroids, cyclosporine A, tacrolimus, methotrexate, and anti-inflammatory biologics into the affected ocular and salivary glands. Degradable polymers including PLGA, PEG, chitosan, and polycaprolactone are often used due to their pharmacodynamic advantages and safe characteristics. These nanoparticles enhance the effectiveness of treatment by increasing the blood circulation time, improving cellular internalization, and providing extended drug release in affected inflammatory glandular tissues. Additionally, surface functionalization with ligands or antibodies helps in achieving selective targeting of activated immune cells, resulting in reduced side effects on systemic immunity.^132,133 Polymeric nanomicelles have exhibited potential for treating ocular symptoms related to SS-induced dry eye syndrome. The hydrophobic nature of the polymeric system facilitates the incorporation of hydrophobic drugs like cyclosporine A while enhancing the permeation of the cornea and precorneal retention of the drug. Polymeric micelles have been reported to provide greater tear film stability and inhibition of inflammatory cytokines released from ocular tissue relative to regular ophthalmic solutions. pH-responsive, oxidation-responsive, and enzyme-responsive polymeric nanoparticles have been synthesized for releasing active molecules in response to changes in pH, oxidative environment, or enzymes in an autoimmune microenvironment. These stimuli-responsive polymers could eventually facilitate targeted immunotherapeutic strategies for SS.^134–136

Lipid-Based Nanocarriers (Liposomes, Solid Lipid Nanoparticles)

Nanocarriers such as liposomes and solid lipid nanoparticles (SLNs) also constitute an important class of nanoplatforms used in SS treatment. Liposomes can be defined as phospholipid-based vesicles that can contain both hydrophilic and hydrophobic substances, rendering them very flexible for delivery of immunosuppressive drugs. Due to the similarity between the structure of liposomes and biological membranes, liposome biocompatibility is extremely high. The ability to fuse with epithelial and immune cells further enhances their functionality. Liposomes filled with corticosteroids, tacrolimus, or cyclosporine A have shown an ability to penetrate corneas more easily in ocular SS and increase the duration of treatment. Moreover, liposomal artificial tears were used in SS-associated dry eye disease.^131,137 Solid lipid nanoparticles (SLN) formulations also present additional benefits, such as enhanced physical stability, stabilization of the active components against any degradation, and prolonged drug-release behavior. The use of SLN carriers has gained more interest as potential candidates in the design of both local and systemic immunomodulatory treatment due to their safety profile and ability to increase mucus penetration. For instance, the use of SLN carriers for SS-related ocular disease presents better bioavailability, as well as fewer administration requirements when compared to conventional eye drops. Additionally, lipid-based nanocarriers can be used as potential candidates to deliver nucleic acids such as siRNA or microRNA molecules for the inhibition of inflammatory cytokines and the autoreactive signaling pathways. Hybrids such as cerasome and bicelles that mimic liposomes but have silica nanoparticle properties have been tested.^135,137,138

Inorganic Nanoparticles (Gold, Silica, Cerium Oxide)

Inorganic nanoparticles have been extensively studied in autoimmune nanomedicine because of their distinctive physicochemical properties, imaging, and inherent bioactive features. Gold nanoparticles (AuNPs) exhibit exceptional anti-inflammatory and antioxidative features, and they can be modified with peptides, antibodies, and nucleic acids to modulate the immune system. According to various experimental studies on autoimmune disorders, AuNPs have been found to attenuate the macrophages’ inflammatory process, decrease pro-inflammatory cytokine release, and inhibit NF-κB pathways. Furthermore, surface plasmon resonance attributes give AuNPs the ability to be used theranostically as both imaging and therapeutic agents. In SS, AuNPs are currently being explored as carriers of anti-inflammatory drugs.^132,137

Mesoporous silica nanoparticles (MSN) are another important inorganic carrier system due to their enormous surface area, adjustable pore sizes, and impressive drug-loading ability for biological and chemical entities. MSN allows for controlled and stimulus-dependent drug release, which enables the surface modification for targeted delivery. The use of MSN in inflammatory and autoimmune diseases has shown an effective delivery of immunomodulators with low systemic toxicity. Moreover, hybrid MSNs have been found to be highly structurally stable with enhanced circulation properties, which can be ideal for chronic autoimmune diseases like SS.^136–138 Nanoceria (cerium oxide nanoparticles) has become increasingly popular due to its regenerative antioxidant properties and ROS scavenging abilities. Oxidative stress has been identified as one of the main contributors to epithelial cell injury and chronic inflammation in SS. The nanoceria particles have the capability of changing their oxidation states from Ce³⁺ to Ce⁴⁺, similar to natural antioxidants like superoxide dismutase and catalase. In studies involving ocular inflammatory diseases, it was found that the cerium oxide nanoparticles could offer protection against oxidative damage and also inhibit inflammation without any notable toxicity.^139–141

Biomimetic Nanoparticles

Biomimetic nanoparticles have emerged as an exciting field of nanomedicine, which is based on mimicking biological properties that resemble those of native cells or extracellular vesicles. These biomimetic nanoparticles encompass cell membrane-functionalized nanoparticles, exosome-mimicking nanovesicles, and extracellular vesicles for drug delivery purposes. Biomimetic nanoparticles exhibit superior immune avoidance, long circulation periods, and improved targetability as compared to synthetic nanoparticles. They can be helpful in treating autoimmune diseases by inducing immune tolerance through altering antigen presentation and attenuating immune activation.^131,142,143 Nanoparticles coated with cell membranes obtained from leukocytes, macrophages, or stem cells could be designed to preferentially target inflammatory tissue sites via specific interactions with adhesion molecules and inflammatory chemokines. These approaches might allow the direct delivery of anti-inflammatory compounds to the affected salivary glands without prompt elimination by the reticuloendothelial system. The use of exosome-mimicking nanoparticles represents an attractive approach owing to the natural role of extracellular vesicles in cell-to-cell immune communication. Exosomes isolated from mesenchymal stem cells were found to exhibit immunomodulatory and reparative properties in autoimmune models by modulating Th17 differentiation and promoting regulatory T-cell function. Therefore, biomimetic nanoparticles represent an extremely promising approach for establishing homeostatic conditions and reprogramming autoimmune environments in SS.^131,132

Hydrogel-Based Nano-Systems for Localized Therapy

Nano-systems based on hydrogels have become very promising tools for targeted and prolonged drug delivery in SS due to their ability to hold water, extend drug presence, and deliver drugs in a controlled fashion in ocular and salivary tissues. Hydrogels are three-dimensional polymer frameworks that can absorb considerable amounts of water without losing their shape. The combination of nanoparticles with hydrogels produces multifunctional hybrid nano-scaffolds with enhanced mechanical strength, mucoadhesiveness, and treatment efficacy. This type of nano-system is especially valuable in treating SS-related xerostomia and keratoconjunctivitis sicca.^135,136 Nanohydrogels responsive to changes in the pH levels, temperature, and inflammatory factors have also been designed in order to enable drug release from the encapsulating nanohydrogel particles. For instance, thermoresponsive hydrogels experience a sol-gel phase transformation after their contact with the ocular tissues, thus increasing the retention rate in the precorneal region as well as the availability of the anti-inflammatory agents. Nanohydrogel-composite hydrogel constructs have also been found efficient in salivary gland reconstruction due to their ability to facilitate stem cell viability along with sustained delivery of the cytokines. Furthermore, such nanogels can serve as artificial extracellular matrices for facilitating epithelial restoration and minimizing immune-mediated tissue damage.^135–137 The representative nanoplatforms used in SS for modulation of autoimmune microenvironments are given in Table 1, whereas the advantages, limitations, and clinical stages of platforms like liposomes, PLGA NPs, exosomes, nanoceria, and hydrogels are summarized in Table 2.

Table 1 Representative Nanoplatforms Studied in Sjögren’s Syndrome for Modulation of Autoimmune Microenvironments

Table 2 A Summary of the Advantages, Limitations, and Clinical Stages of Platforms, Including Liposomes, PLGA Nanoparticles, Exosomes, Nanoceria, and Hydrogels

Nanotechnology for Salivary Gland Regeneration

The salivary gland disorder that causes SS is caused by the chronic autoimmune destruction of epithelial cells, gland fibrosis, oxidative stress, and continued lymphocyte invasion. There have been recent innovations in nanomedicine that show great promise in restoring the function and structure of the glands via stem cell delivery, tissue engineering, growth factor release, and immune modulation. Nanotechnology platforms offer better bioavailability, controlled drug release, and targeted tissue delivery.^161,162

The salivary gland epithelium is not a passive target for immune mediated injury, as should be considered in SS. Acinar and ductal epithelial cells actively participate in the modification of the local autoimmune microenvironment via altered secretory function, epithelial stress responses, metabolic dysfunction, impaired ion/water transport, mitochondrial dysfunction, oxidative stress and endoplasmic reticulum stress. Acinar cell injury can lead to a decrease in saliva output, and ductal injury can affect electrolyte transport, epithelial barrier function, antigen presentation, and recruitment of immune cells via chemokines. Furthermore, neuroepithelial regulation is necessary for glandular secretion, since the autonomous signaling plays a role in acinar fluid secretion, protein release and epithelial homeostasis. A disruption of these epithelial and neural regulatory pathways could thus enhance the hypofunction of the glands and the activation of the local immune system.^161–163

If such strategies based on nanotechnology are tailored to work in this glandular epithelial niche, they may prove to be particularly relevant. These may include different nanocarriers for targeting the epithelium for local delivery of anti-inflammatory agents, antioxidant nanoparticles to counteract oxidative and mitochondrial stress, nucleic-acid delivery systems to intervene with interferon or chemokine related pathways, and hydrogel based local depots to maintain therapeutic exposure in salivary or lacrimal tissue. But these strategies are largely conceptual in SS and need to be assessed in disease-specific models incorporating not only an assessment of immune suppression, but also epithelial viability, acinar and ductal function, salivary secretion, neuroepithelial signaling, biodistribution, and long-term safety.^144,164,165

Stem Cell Delivery via Nanocarriers

Regenerative treatment using stem cells appears to be an effective approach to repair salivary glands in SS patients based on the ability of MSCs, SG progenitor cells, and iPSCs to self-renew and exert immunomodulatory effects. The conventional stem cell transplantation often encounters problems related to poor survival rate, rapid clearance by immune cells, and inability to adapt to inflammatory surroundings. This has led to the development of nanoparticulates such as poly(lactic-co-glycolic acid) nanoparticles, chitosan nanoparticles, and hyaluronic acid derivatives that will increase the success rate of the stem cells.¹⁶⁶ The use of magnetic nanoparticles for the effective delivery of stem cells has increased efficiency due to the localization of these cells, which are attracted to specific locations using magnetic navigation. This ensures that stem cells accumulate around the glands that have inflammation. In addition, the use of exosome nanotherapy, which relies on mesenchymal stem cells, is effective for regeneration and immunomodulation, since exosomes have bioactive compounds such as lipids, miRNAs, and proteins that promote epithelial cell repair and inflammatory mediator inhibition.¹⁶²

Growth Factor Encapsulation Strategies

Epithelial growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF) play important roles in the regeneration process for epithelial cells, angiogenesis, and tissue remodeling. The use of these growth factors in clinical settings is restricted due to their quick metabolic degradation and biological instability. Various nanotechnology strategies, including liposomes, polymer-based nanoparticles, nanogels, and hydrogels, have been developed to deliver regenerative agents locally in damaged salivary glands.¹⁶¹ Controlled release systems can protect growth factors from enzymatic breakdown, allowing them to maintain therapeutic levels over extended periods of time. One of the most viable methods for achieving tissue regeneration through the use of nanosystems that have been injected includes the use of hydrogels and nanoparticles as they help provide mechanical stability and ensure sustained delivery of the regenerative compounds. The gene-activated nanocarriers that are able to deliver plasmid DNA or messenger RNA encoding regenerative compounds are another novel method for tissue regeneration.¹⁶²

Tissue Engineering and Nanoscaffolds

Nanotechnology-assisted tissue engineering has brought about remarkable progress in regenerative medicine of salivary glands owing to the capacity of forming biologically inspired scaffolds which mimic natural extracellular matrix. Nanofibrous structures, peptide-based nanoparticles, collagen-based matrices, and hydrogel nanocomposites offer highly porous three-dimensional environments that promote cellular activities such as attachment, growth, migration, and acinar differentiation. Nanoscaffolds may also be used to deliver various therapeutic agents including growth factors, anti-inflammatory drugs, and antioxidants to regenerate tissues.¹⁶⁶ Electrospinning methods have allowed for the development of nanofiber constructs employing biomaterials like collagen, gelatin, silk fibroin, chitosan, and polycaprolactone, all of which possess desirable biocompatibility and mechanical characteristics. Injectable nanocomposites with hydrogel matrices are particularly beneficial since they can adapt to glandular abnormalities while sustaining hydrated conditions that promote epithelial development and stem cell viability. Emerging innovations in the realm of three-dimensional bioprinting with nanomaterials might eventually result in the production of functional salivary gland replacements that can restore normal secretion in SS sufferers with severe glandular damage.¹⁶⁷

Regenerative Immunomodulation

Salivary gland regeneration therapy in SS is possible only if chronic inflammation caused by autoimmunity is controlled. Thus, immunomodulatory approaches have been widely researched in recent years as a key element of nanomedicine applications. Nanoparticles can be designed to introduce anti-inflammatory cytokines, immunosuppressive substances, antioxidants, and tolerance-inducing components into glandular tissues invaded by lymphoid aggregates while simultaneously activating regenerative pathways.¹⁶¹ Nanomaterials with immunomodulating and inherent antioxidant characteristics like CeO₂ nanoparticles and biomimetic extracellular vesicles have been found promising for lowering oxidative stress, preventing inflammatory cytokine secretion, and shifting macrophages towards an anti-inflammatory M2 type. This leads to improved epithelial defense, remodeling of the extracellular matrix, and the recovery of the normal function of glands. As a result, nanotherapy for regenerative medicine involves tissue engineering, immunomodulation, and drug delivery systems that can enhance the results of SS treatment significantly.¹⁶²

Preclinical and Clinical Advances

Advancements made in the use of nanotechnology in therapies for SS have helped to speed up the shift from mechanism-focused research at the lab bench level to translational medicine and early clinical applications.^4,168 The pathophysiology of the autoimmune microenvironment of SS is very complicated and entails dysfunctional interactions between the immune system and epithelium.^2,38 Hence, accurate modeling of glandular inflammation and remodeling in preclinical studies is necessary to assess the effectiveness and safety of nanotherapies.^161,169 Innovative developments in organoid fabrication, microfluidic technology, animal models, and immunomodulation using nanoparticles have led to significant advancements in the comprehension of disease progression as well as treatment strategies.^2,4

In vitro Models of Sjögren’s Microenvironment

Classic two-dimensional cultures of epithelial cells have a very poor capability for reproducing the intricate interaction between cells seen in patients of SS. Hence, more complex three-dimensional organoids, salivary gland spheroids, and chip-based organs are being used to replicate the autoimmune microenvironment. The salivary gland organoids generated using stem cells or progenitors retain the integrity of the epithelial polarity, differentiation of acinus, and secretion, thus permitting an analysis of the inflammatory pathway and kinetics of nanoparticle entry. Studies showed that the use of organoid-based model accurately replicated the interferon-induced activation of the epithelium and immune cell infiltration in salivary glands affected by SS.^2,170,171 The microfabrication techniques have also made it possible to develop salivary gland-on-a-chip models that include the extracellular matrix, endothelial cells, and immune cells. The bioengineered model mimics the flow of fluids, gradients of cytokines, and epithelial-stromal interactions linked with chronic autoimmune inflammation. The tissue engineering approach is especially beneficial in studying nanoparticle delivery, targeted drug delivery, and exosomal intercellular communication. In addition, the in vitro models help in reducing animal testing and expedite the preclinical evaluation of nanomedicines against salivary gland disorders.^38,172

Animal Models and Nanotherapy Outcomes

Multiple murine models have been created in order to examine the immunopathogenesis of Sjögren syndrome and for evaluating the nanotechnology-based therapies for this disease. Non-obese diabetic (NOD) mice, C57BL/6. NOD-Aec1Aec2 mice, and induced models of experimental Sjögren syndrome display salivary gland infiltration of lymphocytes, decreased salivary flow, the presence of autoantibodies, and epithelial cell death, similar to human Sjögren syndrome. These animal models have been widely employed in the assessment of immunotherapy and regenerative strategies utilizing nanoparticles. Targeted delivery by nanoparticles results in increased uptake by inflamed salivary glands, hence minimizing side effects.^173,174

Exosomes from mesenchymal stem cells and polymeric nanoparticles containing anti-inflammatory drugs have resulted in successful results when tested on animals through inhibition of Th1/Th17 cell reactions, decrease in pro-inflammatory cytokine levels, and restoration of glandular secretion capacity. Lipid and hydrogel nanoparticles have also been used for delivery of growth factors responsible for regenerating the epithelium and acinar cells in glands. Nanoparticles have also been seen to control the polarity of macrophages and inhibit hyperactivity of B-cells in salivary glands.^82,175

Moreover, the application of nanotech biomaterials has also been combined with approaches in regenerative medicine to boost the engraftment capacity of salivary gland cells. It has been observed that in vivo studies using biomimetic scaffolds containing either nanofibers or an extracellular matrix-like scaffold increase the process of vascularization, differentiation, and integration post-transplantation. These findings indicate that through the use of nanotechnology, many challenges faced by existing systemic immunosuppressive approaches can be avoided.¹⁷⁶

Ongoing and Completed Clinical Trials

The clinical application of nanotechnology in the treatment of SS is still at an early stage. However, some potential therapies based on nanotechnology are currently advancing through the preclinical and clinical testing process. The ongoing clinical trials mainly comprise biologics, B-cell inhibitors, stem cell therapies, and exosomes targeting modulation of the immune response and gland repair. Nanotechnology has increasingly become a part of these therapies, which use innovative drug delivery methods, biomarker detection devices, and regenerative tissue scaffolds. Some studies have been conducted using extracellular vesicles produced by mesenchymal stem cells, as they have the ability to modulate the immune response and regenerate damaged tissue. The size of the exosomes themselves is within the range of nanotechnology, providing effective tissue penetration and microRNA delivery. Moreover, there are diagnostic tools utilizing nanoparticles for detecting salivary autoantibodies and inflammatory mediators.^38,82 A number of biological agents that target B cell activation factor, CD40 pathway, and Fc receptor pathway have demonstrated promising outcomes in recent clinical trials of SS patients. These treatments, however, are not strictly restricted to nanotechnology. Their combination with nanocarrier technology is likely to increase pharmacokinetic properties and tissue targeting ability in the future. Moreover, increasing research in personalized treatment will make nanotechnology even more important in autoimmune diseases.^2,176

Translational Challenges

Despite significant advances made thus far, several translational bottlenecks still persist and hinder the practical application of nanotechnology within SS. First, one of the critical challenges is associated with the heterogeneity in the presentation and immune phenotypes of patients, resulting in problems of uniform patterns of response to treatment. The other important concern relates to limited understanding of nanoparticle biodistribution, safety, immunogenicity, and clearance. Variations in the parameters of nanoparticles, such as size, chemistry, and synthesis method, can significantly influence the safety and efficacy of nanoparticles.^177,178 Inability to properly mimic the human autoimmune condition in currently available animal models constitutes another essential limitation, making it difficult to predict the effectiveness of nanoparticles in human subjects. The scalability, regulation, and reproducibility of multifunctional nanoparticles are also major barriers in this field. Finally, the interaction between nanoparticles and the immune system should be carefully optimized to prevent unwanted inflammation or immunosuppression.^175,176 Any future success would most probably rely on the collaboration of researchers across different disciplines, including immunology, biomaterials science, rheumatology, and bioengineering. Artificial intelligence, precision nanomedicine, and use of patient-specific organoids could also make the process more efficient and personalized.

Future Perspectives

Future efforts towards the development of nanotechnology-based therapy against SS will rely on the combination of the principles of artificial intelligence (AI), precision medicine, biologics-based therapy, and multifunctional nanoparticle engineering.¹⁷⁹ The current approaches toward treatment are limited by the failure to effectively address the specific aspects that underlie the disease, providing only symptom alleviation and general suppression of the immune response instead of selective reprogramming of the autoimmune microenvironment. Nanomedicine techniques developed in this context aim at achieving targeted action on affected tissues, increasing treatment efficiency, and restoring physiological function of the salivary glands without causing systemic adverse effects.^180,181

AI-Guided Nanomedicine Design

The applications of AI and machine learning (ML) have been viewed as revolutionary tools for the synthesis of nanomedicine. The application of AI computational modeling would enable the analysis of multidimensional data acquired through the application of technology such as transcriptomics, proteomics, and immune profiling to elucidate the pathways related to the pathogenesis of SS. So, it is feasible to optimally modify nanoparticle characteristics like size, charge, ligand density, and drug cargo content, leading to an increase in targeting effectiveness and pharmacokinetics. Furthermore, ML can provide information on biodistribution, cell uptake, and immunotoxicity of nanoparticles, thus reducing time in experimental procedures.¹⁸²

Personalized and Precision Nanotherapy

The enormous heterogeneity present in SS requires the synthesis of a customized therapeutic approach to address the specific immune dysfunctions that occur with SS. The use of precision nanomedicine enables regulating the therapy according to the patient-specific information available through the use of molecular biomarkers, inflammation markers, and glandular alterations identified by means of omics approaches and single-cell sequencing. Eventually, salivary gland organoids from the patients themselves along with immune profiling could facilitate testing nanotherapies prior to their clinical administration.^183,184 The nanocarriers modified with tissue-targeting ligands may be able to selectively localize to the inflamed salivary glands or pathogenic immune cells, resulting in high local drug concentrations and decreased systemic toxicity. Moreover, biomarker-activated nanocarriers, which have the capacity to release their therapeutic cargo in response to inflammation or oxidative stress, allow for spatiotemporally controlled drug delivery. Exosome-mediated and RNA-containing nanoparticles are novel nanotherapies with potential use in autoimmune diseases.¹⁸⁵

Combination Therapies (Nanotechnology and Biologics)

A combination of nanotechnology and biologic therapies would be considered a promising strategy for treating SS in the coming years. Biologic treatments against B cells, cytokines, and immune costimulation have shown some success in the treatment of autoimmunity, but their use has been hampered by poor tissue penetration, toxicity issues, and heterogeneous patient response. The use of nanoparticle formulations would help address these issues in terms of biologic stability, controlled release, and targeted delivery.^186,187 In future, nano-biologics would incorporate a mixture of monoclonal antibodies, anti-inflammatory agents, nucleic acid sequences, and growth factors to modulate the autoimmune microenvironment effectively. This approach would aim at inhibition of inflammatory signaling and stimulation of tissue repair, with the goal of stimulating secretory function in the salivary glands. Furthermore, injection of hydrogel nanocomposites for sustained drug delivery locally might be more effective.¹⁸⁸

Conclusion

The SS is a multifactorial autoimmune condition marked by complicated interplays between immune cells, epithelium, cytokines, and metabolism within the autoimmune microenvironment. Current treatments only offer symptomatic relief and immunosuppressive action; therefore, there is an immediate need for effective treatments that directly affect the autoimmune process. The application of nanotechnology can be considered an effective tool for modulating the pathogenic autoimmune microenvironment via selective delivery, modulation of immune cells, regulation of cytokines, reduction of oxidative stress, and restoration of immune tolerance. Moreover, innovations related to bioinspired nanoparticles, exosomes, nanovehicles, and stimulus-responsive approaches open new possibilities for salivary gland tissue regeneration. The combination of artificial intelligence technologies and precision nanomedicine with multifunctional smart nanosystems might advance SS treatments significantly.

Current evidence points to the involvement of pathogenic mechanisms including defective epithelial barrier, interferon activation, B-cell hyperactivity, imbalance of cytokines, oxidative stress, ectopic lymphoid organization and defective tissue repair in disease development. However, the majority of the nanotechnology based strategies have not yet been translated into the clinic, nor into disease specific experimental models of SS. Thus, their effectiveness in the clinic is still not known. The focus of future research should be on preclinical models relevant to SS, targeted delivery to the salivary and lacrimal tissue, evaluation of biodistribution and toxicity, use of pharmacodynamic endpoints in the immune system, biomarker-based patient stratification and well-designed translation studies. As long as such evidence is not provided, nanotechnology should be considered as a hopeful conceptual platform for future research in SS.