Abstract
Joint diseases represent a significant health burden due to their high prevalence and morbidity, yet current treatments fail to provide comprehensive and long-term relief for all patients. In this context, adeno-associated virus (AAV) gene therapy has emerged as a promising approach, offering advantages such as prolonged efficacy and minimal immunogenicity. AAV has been extensively studied for various medical conditions, with some applications successfully implemented in patient treatments. Currently, a few clinical trials utilizing AAV have been completed for treating arthritis. However, challenges such as transduction efficiency, off-targets, and preexisting immune responses persist. This review provides an overview of the current paradigms of treatment with regard to joint diseases, elaborates on the AAV delivery barriers related to application in treating joint diseases, and discusses strategies to improve gene therapy efficacy, including AAV capsid engineering, small molecule-assisted AAV delivery, optimizing tissue-specific or inflammation-inducible promoters, as well as strategies to mitigate immune responses to AAV.