Abstract: Thalassemia is a hereditary hemolytic disorder caused by mutation or deletion in the α-globin gene or β-globin gene, leading to reduced or completely absent synthesis of α-globin peptide chain or β-globin peptide chain. Patients with moderate to severe thalassemia are predominantly dependent on regular blood transfusion therapy; however, this life-sustaining treatment inevitably leads to chronic iron overload, which may progress to potentially fatal complications. Allogeneic hematopoietic stem cell（HSC） transplantation is a curative option for transfusion-dependent thalassemia（TDT）; however, the majority of patients do not have access to HLA-matched donors. Ex vivo gene therapy, employing lentiviral vectors to deliver functional α-or β-globin gene or gene editing autologous HSC, followed by reinfusion into patients, has emerged as a promising alternative curative approach for TDT. While ex vivo gene therapy remains the predominant strategy in current clinical trials, this approach presents several limita-tions, including the adverse effects of myeloablative conditioning regimens, high costs associated with personal-ized manufacturing, intricate logistical requirements, and stringent quality control challenges. In vivo gene therapy for TDT, involving direct modification or gene editing of HSC within the patient’s body, represents a highly promising therapeutic strategy. However, this approach still faces challenges in developing efficient and safe delivery systems. This article reviews recent advances in clinical trials of ex vivo gene therapy for TDT and evaluates various delivery vector systems for in vivo gene therapy, including viral vectors, lipid nanoparticles（LNP）, and virus-like particles（VLP）. We provide a systematic comparison of their respective advantages and limitations, while discussing potential future directions for technological optimization in this field.