Adeno-Associated Virus Gene Therapy for Recurrent and Drug-Resistant Ovarian Cancer: Capsid Engineering, Intraperitoneal Delivery, and Rational Combinations

Ovarian cancer remains difficult to cure because disseminated peritoneal disease, heterogeneity, and resistance to platinum and poly(ADP-ribose) polymerase inhibitors limit treatment durability. Adeno-associated virus (AAV) vectors offer sustained transgene expression and capsid and regulatory cassette engineering, but translation is constrained by incomplete tumor-selective delivery, limited cargo capacity, host immunity, and heterogeneous tumor states. We examine AAV-mediated therapy in the context of recurrent and drug-resistant ovarian cancer. We discuss receptor retargeting, intraperitoneal versus systemic delivery, suicide genes, cytokines, genome editing, tumor suppressor restoration, and secreted antiangiogenic payloads. The most extensive ovarian AAV precedent concerns antiangiogenic and vascular-normalizing approaches; EpCAM-directed delivery and PD-L1-targeted AAV-CRISPR provide early evidence. FOLR1-targeted IL-12 efficacy and immune response findings derive from engineered MC38 colorectal tumors, with ovarian-cell targeting demonstrated separately. Studies do not establish restoration of platinum or PARP inhibitor sensitivity or any clinical benefit in resistant ovarian cancer. Chemotherapy combinations have preclinical support, whereas combinations with PARP inhibitors, checkpoint inhibitors, and antibody-drug conjugates remain hypotheses requiring direct testing. We outline biomarker-informed patient selection, immunological barriers to redosing, manufacturing and regulatory requirements, and a staged clinical development framework. Translation requires clinically representative resistant models and independent validation of delivery, pharmacodynamic activity, and safety before durable benefit can be inferred.