Hyperthermia-Enhanced Adeno-Associated Virus Gene Therapy: Mechanisms, Delivery Technologies, and Translational Potential.

Adeno-associated virus (AAV) gene therapy is a promising therapeutic approach for both inherited and acquired disorders, yet its effectiveness is often limited by barriers that reduce target cell uptake and transgene expression. While body temperature is known to have a significant impact on viral infection, its controlled regulation for AAV gene therapy has been little explored. This article reviews therapeutic hyperthermia, carefully controlled mild heating, as a complementary strategy to improve delivery and expression. Evidence from cell and animal studies suggests that transient mild heating can increase blood flow and vessel permeability, promoting viral entry from the bloodstream into tissues. It can also trigger cellular stress responses that facilitate entry and downstream processing. Heating can also serve as an external switch when combined with heat-responsive genetic control systems, allowing gene expression to be activated only in the heated region. We summarize clinically used methods for delivering local, regional, and whole-body hyperthermia and discuss how spatially controlled heating could be integrated with AAV gene therapy workflows. We also highlight opportunities for clinical translation, key risks, and open questions, including thermal dose control, potential loss of viral particle stability with excessive heating, and the possibility of increased inflammatory or immune side effects.