Next Article in Journal
Can Molecular Pathology Drive Progress in Microbiome Understanding? Lessons from Spousal and Household Studies
Previous Article in Journal
The Role of Whole Slide Imaging in AI-Based Digital Pathology: Current Challenges and Future Directions—An Updated Literature Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JMP
Volume 7
Issue 1
10.3390/jmp7010003
jmp-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Perspective

Peptide-Based Therapeutics in Autoimmune Diseases: Restoring Immune Balance Through Precision

by
Derek Gu
1 and
Vincent Yuan
2,*
1
VitDek Health Solutions, Albuquerque, NM 87110, USA
2
Department of Otolaryngology—Head & Neck Surgery, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15213, USA
*
Author to whom correspondence should be addressed.
J. Mol. Pathol. 2026, 7(1), 3; https://doi.org/10.3390/jmp7010003
Submission received: 24 November 2025 / Revised: 5 January 2026 / Accepted: 7 January 2026 / Published: 8 January 2026
Browse Figures
Versions Notes

Abstract

Autoimmune diseases arise from the loss of antigen-specific tolerance, leading to chronic inflammation and tissue damage. Peptide-based therapeutics provide a precise strategy to restore immune balance by targeting autoreactive lymphocytes and antigen-presenting cells in tolerogenic contexts. These therapies induce regulatory T cells, modulate APC phenotypes, and can interfere with proinflammatory signaling. Advances in delivery technologies, including nanoparticles, lipid nanoparticles, hydrogels, and conjugates, improve peptide stability, co-deliver tolerogenic cues, and enable targeted antigen presentation. mRNA lipid nanoparticle platforms permit in situ expression of peptides or immunomodulatory molecules. Preclinical studies in models of type 1 diabetes, multiple sclerosis, and lupus demonstrate robust antigen-specific tolerance, while early-phase clinical trials show safety and mechanistic engagement. Insights from approved peptide therapies in allergy and other fields underscore the importance of epitope selection, delivery context, and biomarker-guided development. Collectively, these strategies suggest that rationally formulated, precisely targeted peptide therapeutics hold promise for achieving durable immune tolerance in autoimmune disease.

1. Introduction

Autoimmune diseases result from the breakdown of self-tolerance, causing chronic inflammation and tissue damage [1]. Current therapies primarily target inflammatory pathways rather than the underlying loss of antigen-specific regulation, often requiring lifelong treatment and carrying risks of infection and systemic immunosuppression [2,3]. Restoring immune tolerance with precision remains a critical unmet need.
Peptide-based therapeutics offer a targeted approach by presenting defined disease-relevant epitopes to autoreactive lymphocytes and antigen-presenting cells (APCs) in tolerogenic contexts [4,5]. These therapies can fine-tune T-cell receptor signaling, bias APCs toward regulatory phenotypes, and induce regulatory T cells, achieving specificity without broad immunosuppression [6,7]. Advances in peptide design, epitope mapping, and delivery technologies have enhanced control over antigen presentation, cellular targeting, and immune modulation [8]. Technological innovations further expand the potential of peptide therapeutics. Nanoparticles, lipid formulations, and hydrogels enable co-delivery of peptides with tolerogenic cues, improving stability and directing antigens to tolerogenic APC niches [9,10]. mRNA lipid nanoparticles allow in situ expression of peptide antigens or regulatory molecules, linking innate and adaptive tolerance pathways [3,11]. These approaches have reinvigorated the field, providing new strategies to induce durable, antigen-specific tolerance.
This review summarizes the mechanistic basis, delivery strategies, and translational progress of peptide-based therapeutics in autoimmunity. We discuss how peptide design and formulation enhance tolerogenic outcomes, highlight preclinical and early clinical evidence, and draw lessons from other therapeutic areas to inform future development. Together, these insights illustrate how precision peptide therapeutics can shift the paradigm from broad immune suppression toward restoration of immune balance.

2. Mechanisms of Action of Peptide Therapeutics

Peptide-based therapeutics leverage a limited set of immunological levers to restore immune tolerance: they modulate antigen presentation, fine-tune T-cell receptor signaling, bias APCs toward tolerogenic states, or directly interfere with proinflammatory pathways [12,13,14]. Because autoimmune pathology is predominantly driven by antigen-specific lymphocytes and the APC networks that activate them, peptide approaches aim to re-establish tolerance with high specificity while minimizing systemic immunosuppression [15,16]. The following sections summarize the principal mechanisms, highlight key molecular and cellular mediators, and demonstrate how modern delivery platforms enhance each approach (Figure 1).

2.1. Induction of Antigen-Specific Tolerance

Peptide therapeutics often exploit antigen-specific mechanisms to silence autoreactive lymphocytes [17]. When disease-relevant epitopes are presented in non-inflammatory or subimmunogenic contexts, autoreactive T cells can undergo anergy, deletion, or differentiation into regulatory T cells [18,19]. The outcome depends on antigen dose, MHC affinity, and local costimulatory signals [20]. Altered peptide ligands (APLs) further refine TCR signaling to bias T cells toward tolerance rather than activation [21]. Early trials in multiple sclerosis and type 1 diabetes demonstrated proof of concept, emphasizing the importance of precise HLA matching and controlled delivery [22,23]. Modern APL formulations, particularly those encapsulated in tolerogenic nanoparticles or delivered via tolerogenic dendritic cells, address these challenges and improve efficacy [24,25].

2.2. Modulation of Antigen-Presenting Cells and Local Immune Context

APCs determine whether peptide presentation leads to immunity or tolerance [26]. Co-delivery of peptides with tolerogenic adjuvants or via APC reprogramming is a cornerstone of next-generation peptide immunotherapies [27,28]. Systems such as rapamycin-loaded nanoparticles (e.g., ImmTOR) or vitamin D3-conditioned dendritic cells induce tolerogenic phenotypes characterized by reduced CD80/CD86 and increased IL-10, PD-L1, and/or IDO expression, and favor regulatory over effector T-cell priming [29,30,31]. Nanoparticle designs that co-localize antigen and tolerogenic cues to the same APC achieve synchronized signaling and more stable tolerance [25]. This axis bridges innate and adaptive immunity, reflecting in vivo findings that tolerogenic microenvironments, particularly in the spleen and liver, support long-term immune quiescence [32,33].

2.3. Targeting Effector and Regulatory Signaling Pathways

Some peptide therapeutics act independently of antigen specificity by modulating proinflammatory protein interactions or immune checkpoint pathways. Examples include peptides that block cytokine–receptor binding, inhibit NF-κB activation, prevent inflammasome assembly [34,35], or mimic inhibitory ligands in the PD-1/PD-L1 or CTLA-4/CD80 pathways [36]. These strategies allow local suppression of inflammation or enhancement of regulatory signaling without systemic immunosuppression [37]. When combined with antigen-specific peptides, they help establish an immune environment conducive to durable tolerance, particularly in ongoing autoimmune inflammation [38].

2.4. Encoding and Integrated Delivery for Precision Tolerization

Recent advances harness both genetic and material-based delivery strategies. mRNA lipid nanoparticle platforms encoding peptide antigens or tolerogenic mediators such as IL-10 or PD-L1 enable in situ antigen expression and presentation on MHC molecules within targeted APCs [32]. Peptide–MHC multimers, engineered regulatory cells, and fusion constructs including Fc, albumin, or receptor-targeting conjugates allow precise engagement of autoreactive lymphocytes [39]. These approaches integrate durable antigen exposure, cellular targeting, and intrinsic tolerogenic cues, combining antigen-specific and context-specific immunomodulation [38]. Preclinical studies demonstrate robust tolerance induction across models of multiple sclerosis, type 1 diabetes, and lupus, with early-phase clinical translation underway [40].

3. Delivery Platforms and Formulation Strategies

Recent advances in delivery and formulation technologies have significantly enhanced peptide-based immunotherapies for autoimmune diseases. Peptides alone often suffer from rapid clearance, limited targeting, immunogenic variability, and short in vivo persistence, making delivery platform selection critical for achieving antigen-specific tolerance [40,41]. This section highlights four major categories of formulation strategies (Figure 2): (1) nanoparticles, including lipid, polymer, and co-formulations with tolerogenic agents such as rapamycin; (2) mRNA lipid nanoparticle systems encoding peptides or tolerogenic modulators; (3) conjugates, including Fc, albumin, or receptor-targeting moieties; and (4) depot, hydrogel, or oral delivery systems for controlled release and non-invasive administration.

3.1. Nanoparticles

Nanoparticles offer multiple advantages for peptide-based immunomodulation, including payload protection, targeted delivery to APC subsets, and co-delivery of immunomodulatory agents [42,43]. In the murine experimental autoimmune encephalomyelitis model, PLGA nanoparticles encapsulating an inhibitory peptide (LABL binding ICAM-1) and displaying MOG35–55–KKK prevented disease prophylactically and reduced established severity [44]. Mechanistically, this approach decreased dendritic cell MHC II and CD86 expression and limited Th1/Th17 infiltration. Antigen-linked multi-myelin peptide nanoparticles (TIMPs) in relapsing-remitting EAE reduced Th17 cells while increasing Tr1 regulatory cells [44]. Formulation studies emphasize co-encapsulation or surface display of antigen with tolerogenic cues, targeting nanoparticles to tolerogenic APC niches, and material composition, including PLGA, lipid-based, or mesoporous silica, which influence biodistribution, uptake, and immune response [45,46]. Mesoporous nanoparticles incorporating ROS-scavenging cerium oxide improved recovery in late-stage EAE [47]. Dosing strategies, including single versus repeated administration, intravenous versus subcutaneous delivery, and antigen-to-nanoparticle ratios, impact therapeutic efficacy [48]. Clinical translation requires attention to large-scale manufacturing, reproducibility, and human APC variability.

3.2. mRNA Lipid Nanoparticles Encoding Peptides or Tolerogenic Modulators

The success of mRNA lipid nanoparticle vaccines has driven interest in autoimmune applications. These systems enable transient, in situ expression of antigens or tolerogenic mediators, offering programmable immune modulation [3]. LNPs delivering Foxp3 mRNA to CD4+ T cells reprogrammed them into transient regulatory T cell-like populations capable of suppressing effector T cell proliferation [49,50]. Tolerogenic mRNA-LNPs incorporating phosphatidylserine lipids delivered MOG35–55 antigen to splenic APCs, reducing disease severity in EAE [51]. Collectively, these studies highlight the capacity of mRNA-LNP platforms to couple antigen delivery with active immune reprogramming. Advantages include sustained, physiological antigen presentation and co-expression of modulators such as IL-10 or PD-L1, biasing immune responses toward tolerance [52,53].
Safety considerations are particularly important for mRNA-LNP-based therapies in autoimmune populations, where baseline innate immune activation and elevated type I interferon signatures are common [3,54]. Excessive activation of innate sensing pathways could exacerbate disease rather than promote tolerance [55]. Accordingly, emerging strategies to mitigate these risks include immune-inert lipid formulations, careful dose optimization, control of transient expression kinetics, and patient stratification based on baseline interferon and inflammatory profiles. Such approaches will be essential to safely translate mRNA-LNP tolerance platforms into autoimmune clinical settings [52,56].

3.3. Conjugates, Depots, and Hydrogels

Conjugation improves peptide stability, half-life, and targeted delivery by linking peptides to Fc domains, albumin, or tolerogenic receptor ligands [57]. Fc and albumin conjugates extend circulation via neonatal Fc receptor recycling, while ligands targeting DEC205, PD-L1, or Siglecs direct antigens to tolerogenic dendritic cells [58,59,60,61,62]. Depot and hydrogel systems enable controlled, localized antigen release, sustaining presentation in tolerogenic environments while minimizing systemic exposure [63,64]. Polymer depots co-delivering antigen and immunomodulators reversed autoimmune paralysis in mice with a single treatment [65]. Hydrogels can incorporate stabilizing or retention elements, while oral delivery is explored for immune tolerance despite degradation and absorption challenges [66]. Together, these approaches highlight the versatility of conjugation- and depot-based platforms for shaping antigen exposure in space and time. Reproducibility, release kinetics, and regulatory alignment are critical considerations for translation.
Despite their shared goal of promoting tolerogenic antigen presentation, delivery platforms differ substantially in safety profiles, manufacturability, and translational readiness. Polymeric and lipid nanoparticles enable co-delivery of antigen and immunomodulatory cues but may face challenges related to batch-to-batch variability, biodistribution, and off-target uptake [67,68]. mRNA lipid nanoparticles offer programmable and transient antigen expression but raise additional safety considerations, including innate immune activation and interferon responses, particularly in autoimmune populations [69]. In contrast, peptide conjugates such as Fc- or albumin-linked peptides benefit from established manufacturing pipelines and predictable pharmacokinetics, although they may provide more limited control over cell-type–specific targeting [70]. Depot and hydrogel systems provide localized, sustained antigen exposure with reduced systemic risk, yet scalability, reproducibility, and regulatory standardization remain challenges [71]. These distinctions underscore that no single delivery platform is universally optimal, and that platform selection should be guided by disease context, safety requirements, and translational feasibility.

4. Preclinical and Clinical Landscape

The preclinical and clinical landscape highlights progress and challenges in developing antigen-specific tolerance strategies. Animal models are essential for dissecting mechanisms and evaluating therapeutic potential, demonstrating how tailored antigens, often delivered with advanced biomaterials, modulate immune responses and restore regulatory balance [72,73]. Early-phase clinical studies provide evidence of safety, immune engagement, and mechanistic feasibility, exploring platforms such as mRNA-LNPs and tolerogenic cell-based approaches [74,75]. Lessons from approved peptide therapies, including allergy desensitization, inform epitope selection, delivery context, and biomarker-guided development, establishing a foundation for evaluating peptide-based strategies in autoimmune disease [76,77].

4.1. Key Animal-Model Results Across Immune-Related Diseases

In type 1 diabetes, non-obese diabetic mice treated with a tolerogenic vaccine containing multiple islet-derived peptides and cyclosporine A induced IL-10+ and TGF-β+ regulatory T cells, suppressed autoreactive CD4+ responses, and prevented disease onset [78]. In EAE, PLGA nanoparticles loaded with myelin-derived peptides prevented disease development and reduced severity by limiting dendritic cell costimulatory signals and Th1/Th17 infiltration [44,79]. Mesoporous nanoparticles co-delivering antigen and immunomodulatory cues enabled recovery from full paralysis in late-stage disease, accompanied by increased Foxp3+ Tregs and reduced autoreactive T cell and APC infiltration [80]. Together, these animal studies demonstrate that peptide-based tolerance strategies can both prevent disease onset and reverse established pathology under controlled experimental conditions. Despite these advances, translation to human disease remains challenging due to autoimmune complexity, epitope diversity, variable HLA presentation, and ongoing epitope spreading [15].
Importantly, the translational potential of peptide-based tolerance strategies differs substantially across autoimmune diseases. In disorders such as multiple sclerosis and type 1 diabetes, where pathogenic T-cell responses are often directed against a relatively restricted set of dominant autoantigens, antigen-specific peptide therapies have shown more consistent preclinical and early clinical efficacy [16,81,82]. In contrast, diseases such as systemic lupus erythematosus and rheumatoid arthritis involve broader immune dysregulation, including polyclonal autoreactive T and B cells, immune complex formation, and systemic cytokine amplification, which may limit the effectiveness of single-antigen tolerance approaches [83,84]. These disease-specific differences suggest that peptide-based therapies are most likely to succeed when dominant antigenic drivers can be identified early in disease, whereas more heterogeneous autoimmune conditions may require multi-epitope, antigen-agnostic, or combination tolerance strategies [85].
A major limitation of early peptide-based therapies has been epitope spreading, in which ongoing tissue damage and inflammation lead to the emergence of new autoreactive specificities beyond the initially targeted epitope [86]. Clinical trials employing single peptides have demonstrated that while antigen-specific immune modulation can be achieved, disease progression may continue as immune responses diversify [87,88]. Accordingly, next-generation delivery platforms—including multi-epitope nanoparticles, tolerogenic immune-modifying particles, and antigen-presenting-cell–reprogramming strategies—aim to counteract epitope spreading by establishing broader regulatory immune environments rather than silencing individual clones [89,90]. However, whether these approaches can fully overcome epitope spreading in established human autoimmune disease remains an open question, underscoring the need for early intervention and adaptive therapeutic designs.

4.2. Early-Phase Clinical Studies

Early-phase clinical studies are evaluating peptide-based tolerance strategies in humans. Tolerogenic immune-modifying particles (TIMP), PLGA nanoparticles encapsulating antigenic peptides, have advanced to Phase Ib/IIa trials in celiac disease, demonstrating safety, antigen-specific immune modulation, and reduced inflammatory responses [91,92,93]. Additional trials in multiple sclerosis, T1D, and rheumatoid arthritis aim to retrain immune recognition of self-antigens, showing favorable safety profiles and mechanistic engagement, including induction of regulatory T cells and reduced autoreactive T-cell activity [33,94,95,96]. Emerging approaches integrate mRNA-LNP platforms and in vivo CAR-T-like systems, encoding tolerogenic peptides or immune modulators in situ, reflecting a growing convergence between nanotechnology and immunotherapy [97,98]. Consistent with their exploratory nature, these early-phase trials primarily emphasize safety, feasibility, and mechanistic biomarker readouts, often enrolling HLA-typed participants early in disease to maximize the likelihood of inducing immune tolerance.
Biomarker-guided development is critical for evaluating peptide-based tolerance therapies. Candidate biomarkers include expansion of antigen-specific regulatory T cells, shifts in cytokine profiles toward IL-10 and TGF-β dominance, reduced expression of costimulatory molecules on antigen-presenting cells, suppression of autoreactive T-cell proliferation, changes in autoantibody titers, and modulation of transcriptional interferon signatures [99,100,101,102]. Together, these biomarkers provide mechanistic insight into target engagement and can inform early go/no-go decisions, dose optimization, and patient selection strategies.
It is important to distinguish proof-of-mechanism signals from evidence of clinical efficacy in current human studies. Most peptide-based tolerance trials to date are early-phase investigations designed to demonstrate safety and antigen-specific immune engagement—such as induction of regulatory T cells, suppression of autoreactive T cell responses, or modulation of inflammatory biomarkers—rather than durable clinical benefit [103,104,105]. Accordingly, while these studies provide strong mechanistic validation, consistent and sustained clinical efficacy has yet to be demonstrated and will require larger, longer-term trials incorporating clinically meaningful endpoints.

4.3. Lessons from Approved Peptide Therapies

Approved peptide therapies in allergy desensitization provide insights for autoimmune applications [106]. Controlled peptide exposure retrains immune responses when delivered in an appropriate context [107]. Critical considerations include identifying disease-relevant epitopes with defined HLA restriction and TCR specificity, ensuring tolerogenic delivery, and employing biomarkers to monitor immune engagement [108,109]. Practical considerations, such as manufacturing, formulation stability, and regulatory compliance for complex peptide–nanoparticle products, must be addressed early [110]. While no antigen-specific peptide therapy is yet approved for autoimmune disease, lessons from other fields highlight the importance of formulation design, precise targeting, and integration of mechanistic and translational insights for durable immune tolerance [111].
Although peptide-based tolerance strategies primarily target T-cell–mediated immunity, their effects can extend to B-cell responses indirectly through modulation of T follicular helper cells, germinal center dynamics, and tolerogenic antigen presentation [112,113]. In diseases such as lupus and rheumatoid arthritis, where autoantibody production and immune complexes are central to pathology, altering T cell–B cell interactions may reduce ongoing B-cell activation and affinity maturation [114,115]. However, current peptide-based approaches have limited capacity to directly eliminate long-lived plasma cells or established B cell memory, representing an important therapeutic limitation [116,117]. Accordingly, future strategies may require combination approaches that integrate antigen-specific peptide tolerance with therapies targeting pathogenic B cell compartments.

5. Conclusions

Peptide-based therapeutics offer a precise approach to restoring immune balance in autoimmune diseases by targeting disease-relevant epitopes, modulating antigen-presenting cells, and promoting regulatory T cell responses. Advances in delivery platforms—including nanoparticles, lipid nanoparticles, hydrogels, conjugates, and mRNA-based systems—enhance peptide stability, control antigen presentation, and enable co-delivery of tolerogenic cues, thereby supporting durable and antigen-specific immune tolerance. Preclinical studies across multiple autoimmune models have demonstrated robust efficacy, and early-phase clinical trials indicate favorable safety profiles and mechanistic engagement. However, several unresolved challenges remain, including epitope spreading, HLA heterogeneity, disease-stage dependence, and interpatient immune variability, which limit the effectiveness of single-epitope approaches and complicate clinical trial design. Overcoming these challenges will require patient stratification based on HLA type, dominant immune pathways, and baseline inflammatory or interferon signatures, alongside the development of multi-epitope formulations, adaptive treatment strategies, and biomarker-guided clinical development to achieve durable, personalized immune tolerance.

Author Contributions

Conceptualization, D.G. and V.Y.; writing—original draft preparation, D.G. and V.Y.; writing—review and editing, D.G. and V.Y.; visualization, D.G.; supervision, V.Y.; project administration, V.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

Author Derek Gu was employed by the company VitDek Health Solutions. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Theofilopoulos, A.N.; Kono, D.H.; Baccala, R. The multiple pathways to autoimmunity. Nat. Immunol. 2017, 18, 716–724. [Google Scholar] [CrossRef]
  2. Jung, S.M.; Kim, W.U. Targeted Immunotherapy for Autoimmune Disease. Immune Netw. 2022, 22, e9. [Google Scholar] [CrossRef]
  3. Razavi, R.; Kegel, M.; Muscat-Rivera, J.; Weissman, D.; Melamed, J.R. Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases. Mol. Ther. Methods Clin. Dev. 2025, 33, 101566. [Google Scholar] [CrossRef]
  4. Yu, X.; Mai, Y.; Wei, Y.; Yu, N.; Gao, T.; Yang, J. Therapeutic potential of tolerance-based peptide vaccines in autoimmune diseases. Int. Immunopharmacol. 2023, 116, 109740. [Google Scholar] [CrossRef]
  5. Wang, B.; Chen, S.; Zheng, Q.; Liu, Y.; Shi, G. Peptide-Based Vaccination Therapy for Rheumatic Diseases. J. Immunol. Res. 2020, 2020, 8060375. [Google Scholar] [CrossRef] [PubMed]
  6. Offner, H.; Hashim, G.A.; Vandenbark, A.A. T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. Science 1991, 251, 430–432. [Google Scholar] [CrossRef] [PubMed]
  7. Szeto, C.; Zareie, P.; Wirasinha, R.C.; Zhang, J.B.; Nguyen, A.T.; Riboldi-Tunnicliffe, A.; La Gruta, N.L.; Gras, S.; Daley, S.R. Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus. Nat. Commun. 2022, 13, 4951. [Google Scholar] [CrossRef] [PubMed]
  8. Black, M.; Trent, A.; Tirrell, M.; Olive, C. Advances in the design and delivery of peptide subunit vaccines with a focus on toll-like receptor agonists. Expert. Rev. Vaccines 2010, 9, 157–173. [Google Scholar] [CrossRef]
  9. Yen, J.H.; Chang, C.C.; Wu, T.Y.; Yang, C.H.; Hsu, H.J.; Liou, J.W. Therapeutic peptides and their delivery using lipid-based nanoparticles. Tzu Chi Med. J. 2025, 37, 223–234. [Google Scholar] [CrossRef]
  10. Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 2021, 20, 101–124. [Google Scholar] [CrossRef]
  11. Cao, W.; Xia, T. mRNA lipid nanoparticles induce immune tolerance to treat human diseases. Med. Rev. 2023, 3, 180–183. [Google Scholar] [CrossRef]
  12. Urbonaviciute, V.; Romero-Castillo, L.; Xu, B.; Luo, H.; Schneider, N.; Weisse, S.; Do, N.N.; Oliveira-Coelho, A.; Fernandez Lahore, G.; Li, T.; et al. Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis. Proc. Natl. Acad. Sci. USA 2023, 120, e2218668120. [Google Scholar] [CrossRef] [PubMed]
  13. Singh, R.P.; Bischoff, D.S.; Singh, S.S.; Hahn, B.H. Peptide-based immunotherapy in lupus: Where are we now? Rheumatol. Immunol. Res. 2023, 4, 139–149. [Google Scholar] [CrossRef] [PubMed]
  14. Pugliese, A. Peptide-based treatment for autoimmune diseases: Learning how to handle a double-edged sword. J. Clin. Investig. 2003, 111, 1280–1282. [Google Scholar] [CrossRef]
  15. Kenison, J.E.; Stevens, N.A.; Quintana, F.J. Therapeutic induction of antigen-specific immune tolerance. Nat. Rev. Immunol. 2024, 24, 338–357. [Google Scholar] [CrossRef]
  16. Faas, P.P.M.; Scharmann, S.D.; Pishesha, N. Antigen-Specific Tolerance: Clinical and Preclinical Approaches in Autoimmunity. Eur. J. Immunol. 2025, 55, e70067. [Google Scholar] [CrossRef]
  17. Mahadik, R.; Kiptoo, P.; Tolbert, T.; Siahaan, T.J. Immune Modulation by Antigenic Peptides and Antigenic Peptide Conjugates for Treatment of Multiple Sclerosis. Med. Res. Arch. 2022, 10, 10–18103. [Google Scholar] [CrossRef]
  18. Hosseinalizadeh, H.; Rabiee, F.; Eghbalifard, N.; Rajabi, H.; Klionsky, D.J.; Rezaee, A. Regulating the regulatory T cells as cell therapies in autoimmunity and cancer. Front. Med. 2023, 10, 1244298. [Google Scholar] [CrossRef]
  19. Pearson, R.M.; Casey, L.M.; Hughes, K.R.; Miller, S.D.; Shea, L.D. In vivo reprogramming of immune cells: Technologies for induction of antigen-specific tolerance. Adv. Drug Deliv. Rev. 2017, 114, 240–255. [Google Scholar] [CrossRef]
  20. Sun, L.; Su, Y.; Jiao, A.; Wang, X.; Zhang, B. T cells in health and disease. Signal Transduct. Target. Ther. 2023, 8, 235. [Google Scholar] [CrossRef] [PubMed]
  21. Faith, A.; Akdis, C.A.; Akdis, M.; Joss, A.; Wymann, D.; Blaser, K. An altered peptide ligand specifically inhibits Th2 cytokine synthesis by abrogating TCR signaling. J. Immunol. 1999, 162, 1836–1842. [Google Scholar] [CrossRef]
  22. Spear, T.T.; Wang, Y.; Smith, T.W., Jr.; Simms, P.E.; Garrett-Mayer, E.; Hellman, L.M.; Baker, B.M.; Nishimura, M.I. Altered Peptide Ligands Impact the Diversity of Polyfunctional Phenotypes in T Cell Receptor Gene-Modified T Cells. Mol. Ther. 2018, 26, 996–1007. [Google Scholar] [CrossRef]
  23. Candia, M.; Kratzer, B.; Pickl, W.F. On Peptides and Altered Peptide Ligands: From Origin, Mode of Action and Design to Clinical Application (Immunotherapy). Int. Arch. Allergy Immunol. 2016, 170, 211–233. [Google Scholar] [CrossRef]
  24. Lin, G.; Wang, J.; Yang, Y.G.; Zhang, Y.; Sun, T. Advances in dendritic cell targeting nano-delivery systems for induction of immune tolerance. Front. Bioeng. Biotechnol. 2023, 11, 1242126. [Google Scholar] [CrossRef]
  25. Qin, X.; Zhang, M.; Liang, J.; Xu, S.; Fu, X.; Liu, Z.; Tian, T.; Song, J.; Lin, Y. Nanoparticles encapsulating antigenic peptides induce tolerogenic dendritic cells in situ for treating systemic lupus erythematosus. J. Control. Release 2025, 380, 943–956. [Google Scholar] [CrossRef]
  26. Garza, K.M.; Chan, S.M.; Suri, R.; Nguyen, L.T.; Odermatt, B.; Schoenberger, S.P.; Ohashi, P.S. Role of antigen-presenting cells in mediating tolerance and autoimmunity. J. Exp. Med. 2000, 191, 2021–2027. [Google Scholar] [CrossRef]
  27. Shae, D.; Baljon, J.J.; Wehbe, M.; Christov, P.P.; Becker, K.W.; Kumar, A.; Suryadevara, N.; Carson, C.S.; Palmer, C.R.; Knight, F.C.; et al. Co-delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines. ACS Nano 2020, 14, 9904–9916. [Google Scholar] [CrossRef] [PubMed]
  28. Baljon, J.J.; Kwiatkowski, A.J.; Pagendarm, H.M.; Stone, P.T.; Kumar, A.; Bharti, V.; Schulman, J.A.; Becker, K.W.; Roth, E.W.; Christov, P.P.; et al. A Cancer Nanovaccine for Co-Delivery of Peptide Neoantigens and Optimized Combinations of STING and TLR4 Agonists. ACS Nano 2024, 18, 6845–6862. [Google Scholar] [CrossRef] [PubMed]
  29. Kishimoto, T.K. Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies. Front. Immunol. 2020, 11, 969. [Google Scholar] [CrossRef]
  30. Ilyinskii, P.O.; Roy, C.J.; LePrevost, J.; Rizzo, G.L.; Kishimoto, T.K. Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles. Front. Immunol. 2021, 12, 637469. [Google Scholar] [CrossRef] [PubMed]
  31. Ferreira, G.B.; Vanherwegen, A.S.; Eelen, G.; Gutierrez, A.C.F.; Van Lommel, L.; Marchal, K.; Verlinden, L.; Verstuyf, A.; Nogueira, T.; Georgiadou, M.; et al. Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways. Cell Rep. 2015, 10, 711–725. [Google Scholar] [CrossRef]
  32. Liu, Y.; Liu, Q.; Zhang, B.; Chen, S.; Shen, Y.; Li, Z.; Zhang, J.; Yang, Y.; Li, M.; Wang, Y. Generation of tolerogenic antigen-presenting cells in vivo via the delivery of mRNA encoding PDL1 within lipid nanoparticles. Nat. Biomed. Eng. 2025, 9, 1320–1334. [Google Scholar] [CrossRef]
  33. Pearson, R.M.; Podojil, J.R.; Shea, L.D.; King, N.J.C.; Miller, S.D.; Getts, D.R. Overcoming challenges in treating autoimmuntity: Development of tolerogenic immune-modifying nanoparticles. Nanomedicine 2019, 18, 282–291. [Google Scholar] [CrossRef]
  34. May, M.J.; D’Acquisto, F.; Madge, L.A.; Glockner, J.; Pober, J.S.; Ghosh, S. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science 2000, 289, 1550–1554. [Google Scholar] [CrossRef]
  35. Wang, Y.F.; Xu, X.; Fan, X.; Zhang, C.; Wei, Q.; Wang, X.; Guo, W.; Xing, W.; Yu, J.; Yan, J.L.; et al. A cell-penetrating peptide suppresses inflammation by inhibiting NF-kappaB signaling. Mol. Ther. 2011, 19, 1849–1857. [Google Scholar] [CrossRef]
  36. Liu, H.; Zhao, Z.; Zhang, L.; Li, Y.; Jain, A.; Barve, A.; Jin, W.; Liu, Y.; Fetse, J.; Cheng, K. Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy. J. Immunother. Cancer 2019, 7, 270. [Google Scholar] [CrossRef] [PubMed]
  37. Bentley, E.R.; Little, S.R. Local delivery strategies to restore immune homeostasis in the context of inflammation. Adv. Drug Deliv. Rev. 2021, 178, 113971. [Google Scholar] [CrossRef]
  38. Satpute, S.R.; Durai, M.; Moudgil, K.D. Antigen-specific tolerogenic and immunomodulatory strategies for the treatment of autoimmune arthritis. Semin. Arthritis Rheum. 2008, 38, 195–207. [Google Scholar] [CrossRef] [PubMed]
  39. Dolton, G.; Zervoudi, E.; Rius, C.; Wall, A.; Thomas, H.L.; Fuller, A.; Yeo, L.; Legut, M.; Wheeler, S.; Attaf, M.; et al. Optimized Peptide-MHC Multimer Protocols for Detection and Isolation of Autoimmune T-Cells. Front. Immunol. 2018, 9, 1378. [Google Scholar] [CrossRef]
  40. Xiao, W.; Jiang, W.; Chen, Z.; Huang, Y.; Mao, J.; Zheng, W.; Hu, Y.; Shi, J. Advance in peptide-based drug development: Delivery platforms, therapeutics and vaccines. Signal Transduct. Target. Ther. 2025, 10, 74. [Google Scholar] [CrossRef]
  41. Wang, Y.; Sun, D.; Laney, V.; Wang, H.; Wang, L.L.; Lu, Z.R. Challenges and opportunities on achieving an adequate delivery efficiency and immunogenicity with peptide-based anticancer vaccines. Adv. Drug Deliv. Rev. 2025, 225, 115675. [Google Scholar] [CrossRef]
  42. Ke, X.; Campbell, B.A.; Lu, X.; Celiker, B.; Zheng, L.; Saung, M.T.; Mao, H.Q. A nanoparticle platform for the co-delivery of multiple antigen epitope peptides and STING agonist to lymph nodes for cancer immunotherapy. Int. J. Pharm. 2025, 680, 125757. [Google Scholar] [CrossRef]
  43. Rana, I.; Oh, J.; Baig, J.; Moon, J.H.; Son, S.; Nam, J. Nanocarriers for cancer nano-immunotherapy. Drug Deliv. Transl. Res. 2023, 13, 1936–1954. [Google Scholar] [CrossRef]
  44. Wang, H.; Shang, J.; He, Z.; Zheng, M.; Jia, H.; Zhang, Y.; Yang, W.; Gao, X.; Gao, F. Dual peptide nanoparticle platform for enhanced antigen-specific immune tolerance for the treatment of experimental autoimmune encephalomyelitis. Biomater. Sci. 2022, 10, 3878–3891. [Google Scholar] [CrossRef] [PubMed]
  45. Liu, Q.; Chen, G.; Liu, X.; Tao, L.; Fan, Y.; Xia, T. Tolerogenic Nano-/Microparticle Vaccines for Immunotherapy. ACS Nano 2024, 18, 5219–5239. [Google Scholar] [CrossRef] [PubMed]
  46. Sun, Z.; Zhao, H.; Ma, L.; Shi, Y.; Ji, M.; Sun, X.; Ma, D.; Zhou, W.; Huang, T.; Zhang, D. The quest for nanoparticle-powered vaccines in cancer immunotherapy. J. Nanobiotechnol. 2024, 22, 61. [Google Scholar] [CrossRef]
  47. Rzigalinski, B.A.; Carfagna, C.S.; Ehrich, M. Cerium oxide nanoparticles in neuroprotection and considerations for efficacy and safety. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1444. [Google Scholar] [CrossRef] [PubMed]
  48. Munter, R.; Christensen, E.; Andresen, T.L.; Larsen, J.B. Studying how administration route and dose regulates antibody generation against LNPs for mRNA delivery with single-particle resolution. Mol. Ther. Methods Clin. Dev. 2023, 29, 450–459. [Google Scholar] [CrossRef]
  49. Thatte, A.S.; Hamilton, A.G.; Nachod, B.E.; Mukalel, A.J.; Billingsley, M.M.; Palanki, R.; Swingle, K.L.; Mitchell, M.J. mRNA Lipid Nanoparticles for Ex Vivo Engineering of Immunosuppressive T Cells for Autoimmunity Therapies. Nano Lett. 2023, 23, 10179–10188. [Google Scholar] [CrossRef]
  50. Sarmah, S.; Baidya, S.; De, M. Recent Advances in Lipid Nanoparticles: Nucleic Acid Therapeutics and Targeting Strategies. Small 2025, 21, e06812. [Google Scholar] [CrossRef]
  51. Gomi, M.; Nakayama, Y.; Sakurai, Y.; Oyama, R.; Iwasaki, K.; Doi, M.; Liu, Y.; Hori, M.; Watanabe, H.; Hashimoto, K.; et al. Tolerogenic Lipid Nanoparticles for Delivering Self-Antigen mRNA for the Treatment of Experimental Autoimmune Encephalomyelitis. Pharmaceuticals 2023, 16, 1270. [Google Scholar] [CrossRef]
  52. Wang, J.; Ding, Y.; Chong, K.; Cui, M.; Cao, Z.; Tang, C.; Tian, Z.; Hu, Y.; Zhao, Y.; Jiang, S. Recent Advances in Lipid Nanoparticles and Their Safety Concerns for mRNA Delivery. Vaccines 2024, 12, 1148. [Google Scholar] [CrossRef] [PubMed]
  53. Reyes-Esteves, S.; Majumder, A.; Marzolini, N.; Zamora, M.E.; Jeong, S.; Wang, Y.; Patel, M.N.; Espy, C.; Papp, T.E.; Akyianu, A.; et al. Targeted lipid nanoparticles containing IL-10 mRNA improve outcomes in experimental intracerebral hemorrhage. J. Neuroinflamm. 2025, 22, 234. [Google Scholar] [CrossRef]
  54. Kiaie, S.H.; Majidi Zolbanin, N.; Ahmadi, A.; Bagherifar, R.; Valizadeh, H.; Kashanchi, F.; Jafari, R. Recent advances in mRNA-LNP therapeutics: Immunological and pharmacological aspects. J. Nanobiotechnol. 2022, 20, 276. [Google Scholar] [CrossRef] [PubMed]
  55. Verbeke, R.; Hogan, M.J.; Lore, K.; Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 2022, 55, 1993–2005. [Google Scholar] [CrossRef]
  56. Yan, Y.; Liu, S.; Wen, J.; He, Y.; Duan, C.; Nabavi, N.; Ashrafizadeh, M.; Sethi, G.; Liu, L.; Ma, R. Advances in RNA-based cancer therapeutics: Pre-clinical and clinical implications. Mol. Cancer 2025, 24, 251. [Google Scholar] [CrossRef]
  57. Frutos, S.; Jordan, J.B.; Bio, M.M.; Muir, T.W.; Thiel, O.R.; Vila-Perello, M. Access to site-specific Fc-cRGD peptide conjugates through streamlined expressed protein ligation. Org. Biomol. Chem. 2016, 14, 9549–9553. [Google Scholar] [CrossRef]
  58. Andersen, J.T.; Dalhus, B.; Viuff, D.; Ravn, B.T.; Gunnarsen, K.S.; Plumridge, A.; Bunting, K.; Antunes, F.; Williamson, R.; Athwal, S.; et al. Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding. J. Biol. Chem. 2014, 289, 13492–13502. [Google Scholar] [CrossRef]
  59. Sand, K.M.; Bern, M.; Nilsen, J.; Noordzij, H.T.; Sandlie, I.; Andersen, J.T. Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics. Front. Immunol. 2014, 5, 682. [Google Scholar] [CrossRef]
  60. Bonifaz, L.; Bonnyay, D.; Mahnke, K.; Rivera, M.; Nussenzweig, M.C.; Steinman, R.M. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 2002, 196, 1627–1638. [Google Scholar] [CrossRef]
  61. Peng, Q.; Qiu, X.; Zhang, Z.; Zhang, S.; Zhang, Y.; Liang, Y.; Guo, J.; Peng, H.; Chen, M.; Fu, Y.X.; et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat. Commun. 2020, 11, 4835. [Google Scholar] [CrossRef]
  62. Loschko, J.; Heink, S.; Hackl, D.; Dudziak, D.; Reindl, W.; Korn, T.; Krug, A.B. Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity. J. Immunol. 2011, 187, 6346–6356. [Google Scholar] [CrossRef]
  63. Mikhail, A.S.; Morhard, R.; Mauda-Havakuk, M.; Kassin, M.; Arrichiello, A.; Wood, B.J. Hydrogel drug delivery systems for minimally invasive local immunotherapy of cancer. Adv. Drug Deliv. Rev. 2023, 202, 115083. [Google Scholar] [CrossRef] [PubMed]
  64. Zheng, J.; Li, X.; He, A.; Zhang, Y.; Yang, Y.; Dang, M.; Li, Q.; Mou, Y.; Dong, H. In situ antigen-capture strategies for enhancing dendritic cell-mediated anti-tumor immunity. J. Control. Release 2025, 385, 113984. [Google Scholar] [CrossRef] [PubMed]
  65. McIlvaine, R.A.; Kapnick, S.M.; Carey, S.T.; Jewell, C.M. Regulation of response to antigen peptides is independent of peptide distribution in lymph node therapeutics. Biomater. Sci. 2025, 13, 5538–5549. [Google Scholar] [CrossRef]
  66. Dongwen, L.; Dapeng, M.; Jiazhi, Y.; Xiaoguang, L. Hydrogels in Oral Disease Management: A Review of Innovations in Drug Delivery and Tissue Regeneration. Med. Sci. Monit. 2025, 31, e946122. [Google Scholar] [CrossRef]
  67. Aslund, A.K.O.; Vandebriel, R.J.; Caputo, F.; de Jong, W.H.; Delmaar, C.; Hyldbakk, A.; Rustique, E.; Schmid, R.; Snipstad, S.; Texier, I.; et al. A comparative biodistribution study of polymeric and lipid-based nanoparticles. Drug Deliv. Transl. Res. 2022, 12, 2114–2131. [Google Scholar] [CrossRef] [PubMed]
  68. Kim, S.; Choi, B.; Kim, Y.; Shim, G. Immune-Modulating Lipid Nanomaterials for the Delivery of Biopharmaceuticals. Pharmaceutics 2023, 15, 1760. [Google Scholar] [CrossRef]
  69. Wei, L.; Dong, C.; Zhu, W.; Wang, B.Z. mRNA Vaccine Nanoplatforms and Innate Immunity. Viruses 2024, 16, 120. [Google Scholar] [CrossRef]
  70. Dean, T.T.; Jelu-Reyes, J.; Allen, A.C.; Moore, T.W. Peptide-Drug Conjugates: An Emerging Direction for the Next Generation of Peptide Therapeutics. J. Med. Chem. 2024, 67, 1641–1661. [Google Scholar] [CrossRef]
  71. Lu, P.; Ruan, D.; Huang, M.; Tian, M.; Zhu, K.; Gan, Z.; Xiao, Z. Harnessing the potential of hydrogels for advanced therapeutic applications: Current achievements and future directions. Signal Transduct. Target. Ther. 2024, 9, 166. [Google Scholar] [CrossRef]
  72. Barre-Sinoussi, F.; Montagutelli, X. Animal models are essential to biological research: Issues and perspectives. Future Sci. OA 2015, 1, FSO63. [Google Scholar] [CrossRef]
  73. Carey, S.T.; Bridgeman, C.; Jewell, C.M. Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps. Adv. Sci. 2023, 10, e2205105. [Google Scholar] [CrossRef] [PubMed]
  74. Raigani, M.; Eftekhari, Z.; Adeli, A.; Kazemi-Lomedasht, F. Advancing gene editing therapeutics: Clinical trials and innovative delivery systems across diverse diseases. Mol. Ther. Nucleic Acids 2025, 36, 102666. [Google Scholar] [CrossRef] [PubMed]
  75. Shi, Y.; Shi, M.; Wang, Y.; You, J. Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications. Signal Transduct. Target. Ther. 2024, 9, 322. [Google Scholar] [CrossRef] [PubMed]
  76. Ali, F.R.; Larche, M. Peptide-based immunotherapy: A novel strategy for allergic disease. Expert Rev. Vaccines 2005, 4, 881–889. [Google Scholar] [CrossRef]
  77. Larche, M.; Wraith, D.C. Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat. Med. 2005, 11, S69–S76. [Google Scholar] [CrossRef]
  78. Zhou, X.; Zhang, S.; Yu, F.; Zhao, G.; Geng, S.; Yu, W.; Wang, X.Y.; Wang, B. Tolerogenic vaccine composited with islet-derived multipeptides and cyclosporin A induces pTreg and prevents Type 1 diabetes in murine model. Hum. Vaccin. Immunother. 2020, 16, 240–250. [Google Scholar] [CrossRef]
  79. Hunter, Z.; McCarthy, D.P.; Yap, W.T.; Harp, C.T.; Getts, D.R.; Shea, L.D.; Miller, S.D. A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease. ACS Nano 2014, 8, 2148–2160. [Google Scholar] [CrossRef]
  80. Nguyen, T.L.; Choi, Y.; Im, J.; Shin, H.; Phan, N.M.; Kim, M.K.; Choi, S.W.; Kim, J. Immunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance. Nat. Commun. 2022, 13, 7449. [Google Scholar] [CrossRef]
  81. Pugliese, A. Autoreactive T cells in type 1 diabetes. J. Clin. Investig. 2017, 127, 2881–2891. [Google Scholar] [CrossRef] [PubMed]
  82. Kaskow, B.J.; Baecher-Allan, C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb. Perspect. Med. 2018, 8, a029025. [Google Scholar] [CrossRef] [PubMed]
  83. Marian, V.; Anolik, J.H. Treatment targets in systemic lupus erythematosus: Biology and clinical perspective. Arthritis Res. Ther. 2012, 14, S3. [Google Scholar] [CrossRef][Green Version]
  84. Kaur, J.; Cairns, E.; Barra, L. Restoring Balance: Immune Tolerance in Rheumatoid Arthritis. J. Rheumatol. 2023, 50, 991–1001. [Google Scholar] [CrossRef]
  85. Peakman, M.; Dayan, C.M. Antigen-specific immunotherapy for autoimmune disease: Fighting fire with fire? Immunology 2001, 104, 361–366. [Google Scholar] [CrossRef]
  86. Vanderlugt, C.L.; Miller, S.D. Epitope spreading in immune-mediated diseases: Implications for immunotherapy. Nat. Rev. Immunol. 2002, 2, 85–95. [Google Scholar] [CrossRef] [PubMed]
  87. Coppieters, K.; von Herrath, M. Antigen-Specific Peptide Immunotherapy for Type 1 Diabetes: Proof of Safety, Hope for Efficacy. Cell Metab. 2017, 26, 595–597. [Google Scholar] [CrossRef][Green Version]
  88. Huurman, V.A.; van der Meide, P.E.; Duinkerken, G.; Willemen, S.; Cohen, I.R.; Elias, D.; Roep, B.O. Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin. Exp. Immunol. 2008, 152, 488–497. [Google Scholar] [CrossRef]
  89. LaMothe, R.A.; Kolte, P.N.; Vo, T.; Ferrari, J.D.; Gelsinger, T.C.; Wong, J.; Chan, V.T.; Ahmed, S.; Srinivasan, A.; Deitemeyer, P.; et al. Tolerogenic Nanoparticles Induce Antigen-Specific Regulatory T Cells and Provide Therapeutic Efficacy and Transferrable Tolerance against Experimental Autoimmune Encephalomyelitis. Front. Immunol. 2018, 9, 281. [Google Scholar] [CrossRef]
  90. Eixarch, H.; Boutitah-Benyaich, I.; Plaza, J.; Rodriguez-Vidal, S.; Salvado, M.; Mancera-Arteu, M.; Almenara-Fuentes, L.; Dalmases, M.; Vives-Pi, M.; Montalban, X.; et al. Reprogramming autoimmunity: Inducing antigen-specific tolerance via apoptotic mimicry in an experimental model of multiple sclerosis. J. Neuroinflamm. 2025, 22, 281. [Google Scholar] [CrossRef]
  91. Kelly, C.P.; Murray, J.A.; Leffler, D.A.; Getts, D.R.; Bledsoe, A.C.; Smithson, G.; First, M.R.; Morris, A.; Boyne, M.; Elhofy, A.; et al. TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study. Gastroenterology 2021, 161, 66–80.e68. [Google Scholar] [CrossRef]
  92. Freitag, T.L.; Podojil, J.R.; Pearson, R.M.; Fokta, F.J.; Sahl, C.; Messing, M.; Andersson, L.C.; Leskinen, K.; Saavalainen, P.; Hoover, L.I.; et al. Gliadin Nanoparticles Induce Immune Tolerance to Gliadin in Mouse Models of Celiac Disease. Gastroenterology 2020, 158, 1667–1681.e12. [Google Scholar] [CrossRef] [PubMed]
  93. Murray, J.A.; Wassaf, D.; Dunn, K.; Arora, S.; Winkle, P.; Stacey, H.; Cooper, S.; Goldstein, K.E.; Manchanda, R.; Kontos, S.; et al. Safety and tolerability of KAN-101, a liver-targeted immune tolerance therapy, in patients with coeliac disease (ACeD): A phase 1 trial. Lancet Gastroenterol. Hepatol. 2023, 8, 735–747. [Google Scholar] [CrossRef]
  94. Streeter, H.B.; Rigden, R.; Martin, K.F.; Scolding, N.J.; Wraith, D.C. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. Neurol. Neuroimmunol. Neuroinflamm. 2015, 2, e93. [Google Scholar] [CrossRef]
  95. Tatovic, D.; McAteer, M.A.; Barry, J.; Barrientos, A.; Rodriguez Terradillos, K.; Perera, I.; Kochba, E.; Levin, Y.; Dul, M.; Coulman, S.A.; et al. Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes. Immunother. Adv. 2022, 2, ltac002. [Google Scholar] [CrossRef] [PubMed]
  96. Sonigra, A.; Nel, H.J.; Wehr, P.; Ramnoruth, N.; Patel, S.; van Schie, K.A.; Bladen, M.W.; Mehdi, A.M.; Tesiram, J.; Talekar, M.; et al. Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis. JCI Insight 2022, 7, e160964. [Google Scholar] [CrossRef]
  97. Chen, Z.; Shu, J.; Hu, Y.; Mei, H. Synergistic integration of mRNA-LNP with CAR-engineered immune cells: Pioneering progress in immunotherapy. Mol. Ther. 2024, 32, 3772–3792. [Google Scholar] [CrossRef]
  98. Wang, J.; Cai, L.; Li, N.; Luo, Z.; Ren, H.; Zhang, B.; Zhao, Y. Developing mRNA Nanomedicines with Advanced Targeting Functions. Nanomicro Lett. 2025, 17, 155. [Google Scholar] [CrossRef]
  99. Fisher, M.S.; Sennikov, S.V. T-regulatory cells for the treatment of autoimmune diseases. Front. Immunol. 2025, 16, 1511671. [Google Scholar] [CrossRef] [PubMed]
  100. Jutel, M.; Akdis, M.; Budak, F.; Aebischer-Casaulta, C.; Wrzyszcz, M.; Blaser, K.; Akdis, C.A. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur. J. Immunol. 2003, 33, 1205–1214. [Google Scholar] [CrossRef]
  101. Kosiewicz, M.M.; Alard, P. Tolerogenic antigen-presenting cells: Regulation of the immune response by TGF-beta-treated antigen-presenting cells. Immunol. Res. 2004, 30, 155–170. [Google Scholar] [CrossRef]
  102. Arif, S.; Tree, T.I.; Astill, T.P.; Tremble, J.M.; Bishop, A.J.; Dayan, C.M.; Roep, B.O.; Peakman, M. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J. Clin. Investig. 2004, 113, 451–463. [Google Scholar] [CrossRef] [PubMed]
  103. Thrower, S.L.; James, L.; Hall, W.; Green, K.M.; Arif, S.; Allen, J.S.; Van-Krinks, C.; Lozanoska-Ochser, B.; Marquesini, L.; Brown, S.; et al. Proinsulin peptide immunotherapy in type 1 diabetes: Report of a first-in-man Phase I safety study. Clin. Exp. Immunol. 2009, 155, 156–165. [Google Scholar] [CrossRef]
  104. Van Rampelbergh, J.; Achenbach, P.; Leslie, R.D.; Ali, M.A.; Dayan, C.; Keymeulen, B.; Owen, K.R.; Kindermans, M.; Parmentier, F.; Carlier, V.; et al. First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes. BMC Med. 2023, 21, 190. [Google Scholar] [CrossRef]
  105. Passerini, L.; Gregori, S. Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases. Front. Immunol. 2020, 11, 2194. [Google Scholar] [CrossRef]
  106. Moldaver, D.; Larche, M. Immunotherapy with peptides. Allergy 2011, 66, 784–791. [Google Scholar] [CrossRef]
  107. Votaw, N.L.; Collier, L.; Curvino, E.J.; Wu, Y.; Fries, C.N.; Ojeda, M.T.; Collier, J.H. Randomized peptide assemblies for enhancing immune responses to nanomaterials. Biomaterials 2021, 273, 120825. [Google Scholar] [CrossRef] [PubMed]
  108. Malviya, M.; Aretz, Z.E.H.; Molvi, Z.; Lee, J.; Pierre, S.; Wallisch, P.; Dao, T.; Scheinberg, D.A. Challenges and solutions for therapeutic TCR-based agents. Immunol. Rev. 2023, 320, 58–82. [Google Scholar] [CrossRef] [PubMed]
  109. Firdessa Fite, R.; Bechi Genzano, C.; Mallone, R.; Creusot, R.J. Epitope-based precision immunotherapy of Type 1 diabetes. Hum. Vaccin. Immunother. 2023, 19, 2154098. [Google Scholar] [CrossRef]
  110. Elsayed, Y.Y.; Kuhl, T.; Imhof, D. Regulatory Guidelines for the Analysis of Therapeutic Peptides and Proteins. J. Pept. Sci. 2025, 31, e70001. [Google Scholar] [CrossRef]
  111. Wang, L.; Wang, N.; Zhang, W.; Cheng, X.; Yan, Z.; Shao, G.; Wang, X.; Wang, R.; Fu, C. Therapeutic peptides: Current applications and future directions. Signal Transduct. Target. Ther. 2022, 7, 48. [Google Scholar] [CrossRef]
  112. Akama-Garren, E.H.; Yin, X.; Prestwood, T.R.; Ma, M.; Utz, P.J.; Carroll, M.C. T cell help shapes B cell tolerance. Sci. Immunol. 2024, 9, eadj7029. [Google Scholar] [CrossRef]
  113. Huang, Q.; Xu, L.; Ye, L. T cell immune response within B-cell follicles. Adv. Immunol. 2019, 144, 155–171. [Google Scholar] [CrossRef]
  114. Christodoulou, M.; Moysidou, E.; Lioulios, G.; Stai, S.; Lazarou, C.; Xochelli, A.; Fylaktou, A.; Stangou, M. T-Follicular Helper Cells and Their Role in Autoimmune Diseases. Life 2025, 15, 666. [Google Scholar] [CrossRef]
  115. Sowerby, J.M.; Rao, D.A. T cell-B cell interactions in human autoimmune diseases. Curr. Opin. Immunol. 2025, 93, 102539. [Google Scholar] [CrossRef] [PubMed]
  116. Winter, O.; Dame, C.; Jundt, F.; Hiepe, F. Pathogenic long-lived plasma cells and their survival niches in autoimmunity, malignancy, and allergy. J. Immunol. 2012, 189, 5105–5111. [Google Scholar] [CrossRef] [PubMed]
  117. DiLillo, D.J.; Hamaguchi, Y.; Ueda, Y.; Yang, K.; Uchida, J.; Haas, K.M.; Kelsoe, G.; Tedder, T.F. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 2008, 180, 361–371. [Google Scholar] [CrossRef] [PubMed]
Jmp 07 00003 g001
Figure 1. Mechanisms and Delivery Strategies of Peptide-Based Therapeutics for Antigen-Specific Tolerization. Peptide-based therapeutics aim to induce antigen-specific tolerance in autoimmune disease by enabling therapeutic peptides to interact with antigen-presenting cells (APCs), generating modified APCs that display the peptides on their surface and promote tolerogenic immune responses. Some peptides also act intracellularly by modulating effector and signaling pathways such as NF-κB, leading to targeted regulation or inhibition of proinflammatory activation. To enhance delivery and therapeutic efficacy, peptides can be formulated using strategies such as nanoparticle encapsulation, peptide–carrier conjugates, or incorporation of tolerogenic adjuvants to enable precise, integrated delivery.
Figure 1. Mechanisms and Delivery Strategies of Peptide-Based Therapeutics for Antigen-Specific Tolerization. Peptide-based therapeutics aim to induce antigen-specific tolerance in autoimmune disease by enabling therapeutic peptides to interact with antigen-presenting cells (APCs), generating modified APCs that display the peptides on their surface and promote tolerogenic immune responses. Some peptides also act intracellularly by modulating effector and signaling pathways such as NF-κB, leading to targeted regulation or inhibition of proinflammatory activation. To enhance delivery and therapeutic efficacy, peptides can be formulated using strategies such as nanoparticle encapsulation, peptide–carrier conjugates, or incorporation of tolerogenic adjuvants to enable precise, integrated delivery.
Jmp 07 00003 g001
Jmp 07 00003 g002
Figure 2. Formulation Approaches Enhancing Stability and Targeted Delivery of Tolerogenic Peptide Therapies. A range of delivery formulation strategies has been developed to address the stability and delivery challenges of tolerogenic peptide therapies. Nanoparticle platforms such as PLGA, lipid, and mesoporous silica nanoparticles protect peptides from degradation and improve absorption. mRNA lipid nanoparticles deliver mRNA to eukaryotic cells to enable in vivo peptide production, resulting in more efficient targeting, navigation, and cellular internalization. Peptide conjugates created by linking peptides to Fc domains, albumin, or tolerogenic receptor ligands further enhance peptide stability and half-life while improving targeted delivery. Depot formulations and hydrogel systems provide an additional approach by enabling sustained and localized release of therapeutic peptides.
Figure 2. Formulation Approaches Enhancing Stability and Targeted Delivery of Tolerogenic Peptide Therapies. A range of delivery formulation strategies has been developed to address the stability and delivery challenges of tolerogenic peptide therapies. Nanoparticle platforms such as PLGA, lipid, and mesoporous silica nanoparticles protect peptides from degradation and improve absorption. mRNA lipid nanoparticles deliver mRNA to eukaryotic cells to enable in vivo peptide production, resulting in more efficient targeting, navigation, and cellular internalization. Peptide conjugates created by linking peptides to Fc domains, albumin, or tolerogenic receptor ligands further enhance peptide stability and half-life while improving targeted delivery. Depot formulations and hydrogel systems provide an additional approach by enabling sustained and localized release of therapeutic peptides.
Jmp 07 00003 g002
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Gu, D.; Yuan, V. Peptide-Based Therapeutics in Autoimmune Diseases: Restoring Immune Balance Through Precision. J. Mol. Pathol. 2026, 7, 3. https://doi.org/10.3390/jmp7010003

AMA Style

Gu D, Yuan V. Peptide-Based Therapeutics in Autoimmune Diseases: Restoring Immune Balance Through Precision. Journal of Molecular Pathology. 2026; 7(1):3. https://doi.org/10.3390/jmp7010003

Chicago/Turabian Style

Gu, Derek, and Vincent Yuan. 2026. "Peptide-Based Therapeutics in Autoimmune Diseases: Restoring Immune Balance Through Precision" Journal of Molecular Pathology 7, no. 1: 3. https://doi.org/10.3390/jmp7010003

APA Style

Gu, D., & Yuan, V. (2026). Peptide-Based Therapeutics in Autoimmune Diseases: Restoring Immune Balance Through Precision. Journal of Molecular Pathology, 7(1), 3. https://doi.org/10.3390/jmp7010003

Article Metrics

Back to TopTop