Interleukin-10(NIAID)

Interleukin-10 (IL-10) is a key immunoregulatory cytokine with potent anti-inflammatory and immunomodulatory functions. Its pleiotropic effects and short half-life, however, have posed challenges for direct therapeutic use. To overcome these hurdles, diverse engineering strategies have been developed to enhance IL-10 stability, tailor its activity, and target its delivery. This review describes the major approaches to IL-10 modification, including fusion proteins (e.g. cytokine/cytokine fusion, IL-10-Fc fusions for half-life extension, and bispecific constructs), encapsulation systems (nanoparticles and hydrogels for sustained or localized release), protein engineering of IL-10 monomers/dimers to modulate receptor engagement (decoupling pro- vs anti-inflammatory signaling), targeted delivery methods (antibody-mediated tissue targeting and intestinal-specific release), and receptor-based fusion proteins (immunoadhesins) to modulate IL-10 signaling. For each strategy, we highlight representative preclinical studies and clinical programs, examining pharmacodynamics, pharmacokinetics, efficacy in disease models (cancer, autoimmunity, colitis, fibrosis, transplantation), and translational potential. Advantages and limitations such as immunogenicity, delivery efficiency, and scalability are critically discussed. These advances collectively illustrate how bioengineering is unlocking IL-10 therapeutic potential while mitigating its prior limitations, paving the way for next-generation cytokine immunotherapies.

Osteoarthritis (OA) is a multifactorial joint disease characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling. Despite its significant global health burden, there are currently no disease-modifying pharmacological therapies for OA. Gene therapy, leveraging viral and non-viral vectors to deliver therapeutic transgenes into the joint environment, shows significant promise. This mini-review highlights recent innovations in OA gene therapy pipelines, focusing on Platforms employing recombinant adenovirus, adeno-associated virus (AAV), and herpes simplex virus vectors. Strategies include AAV-mediated delivery of interleukin-1 receptor antagonist (IL-1Ra) and truncated nkx3.2 transcription factor to modulate inflammation and promote chondrocyte survival. Non-viral approaches, such as plasmid DNA encoding interleukin-10, are also under investigation. Emerging data from preclinical and clinical studies demonstrate the feasibility of achieving sustained, intra-articular transgene expression with therapeutic efficacy in animal models and early-phase human trials. However, challenges persist, including immune barriers to repeat dosing, variability in vector performance, and the high costs of treatment. Additionally, agerelated declines in transduction efficiency, the heterogeneity of OA, and systemic metabolic influences complicate therapeutic outcomes. To overcome current regulatory obstacles, future research must prioritize the refinement of vector systems to enhance safety, potency, and specificity, as well as the development of combination therapies integrating genetic and conventional approaches, targeting pain and improving function. Gene therapy has transformative potential for improving OA management and an important priority is multidisciplinary collaboration to translate preclinical innovations into accessible, effective treatments for a highly heterogeneous and aging patient population.