Conversion of Injectable Cytokines and Immunomodulators into Oral Therapeutic Forms: A Systematic Review of Opportunities, Challenges, and Emerging Drug Delivery Technologies

Abstract

Background: Cytokines and immunomodulators, including Interferon-Alpha (IFN-α), Interferon-Beta (IFN-β), Interleukin-2 (IL-2), and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), are widely used in the management of viral infections, malignancies, autoimmune diseases, and immunodeficiency disorders. However, their clinical application remains limited by the need for parenteral administration, poor patient adherence, systemic adverse effects, and increased healthcare costs. Recent advances in pharmaceutical biotechnology have stimulated interest in developing oral cytokine formulations that improve patient convenience while maintaining therapeutic efficacy.

Objective: This systematic review evaluated the feasibility, efficacy, safety, and technological advances associated with the oral administration of cytokines and immunomodulatory biologics.

Methods: A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases, including PubMed, Scopus, Web of Science, Embase, and Google Scholar, were searched for studies published between January 2000 and June 2026. Studies evaluating oral formulations of IFN-α/β, IL-2, GM-CSF, and related immunomodulatory biologics were included. Data extraction focused on formulation technologies, pharmacokinetics, immunological outcomes, safety profiles, and clinical efficacy.

Results: A total of 1,248 records were identified, of which 62 studies met the eligibility criteria. Nanoparticle-based carriers, liposomal encapsulation systems, enteric-coated formulations, polymeric micelles, and bioadhesive delivery platforms demonstrated significant improvements in cytokine stability and gastrointestinal protection. Oral IFN-α and IL-2 exhibited measurable immunomodulatory effects despite limited systemic absorption. GM-CSF formulations showed promising enhancement of mucosal immune responses and antigen presentation. Most studies reported favorable safety profiles and improved treatment acceptability compared with injectable therapies.

Conclusion: Emerging oral cytokine technologies represent a promising direction in immunotherapy. While challenges related to bioavailability, manufacturing complexity, and regulatory approval remain, continued innovation in drug delivery systems may enable the successful clinical translation of orally administered cytokines and immunomodulators.