Nanobody therapeutics in autoimmune and immune-mediated inflammatory diseases: experimental insights and translational strategies.

Nanobodies, single-domain-based VHHs, are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family that provide marked advantages compared to traditional monoclonal antibodies. Their small molecular size, simple structure, and high antigen-binding affinity facilitate the precise modulation of immune pathways associated with autoimmune pathophysiology. This review integrates ongoing advancements in experimental and translational research on nanobody therapeutics, encompassing multiple autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes. Focus is given to preclinical evaluation using disease models, highlighting critical immunological targets suitable for nanobody-based targeting and assessing data from early-phase clinical trials. An extensive literature review was performed through leading biomedical databases, including Scopus, PubMed, and ClinicalTrials.gov, centered on preclinical studies, disease models, and initial clinical studies available until 2025. Preclinical data support the compelling effectiveness of nanobodies in regulating critical immune targets, including IL-6, BAFF, TNF-α, and integrins, leading to suppression of systemic and tissue-specific inflammatory responses in experimental models. Early-phase studies highlight well-tolerated safety outcomes demonstrating beneficial therapeutic effects, validating the promise of nanobody therapeutics for clinical translation. This detailed synthesis reveals the pathway to clinical translation of nanobody therapeutics in autoimmune diseases, outlining a pathway for subsequent clinical applications and the advancement of next-generation biologic therapies.