Adeno-associated virus (AAV) is a non-enveloped DNA virus infecting a wide variety of species, tissues and cell types, which is recognized as safe and effective method for delivering therapeutic transgenes. AAV vector is the most popular viral gene delivery system in clinical delivery system with unique and multiple advantages, such as tissue tropism, transduction specificity, long-lasting gene expression, low immune responses, without host chromosome incorporation. Till now, four AAV-based gene therapy drugs have already been approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Despite the success of AAV vectors, there still have some remaining challenges to limit the further usage, such as poor packaging capacity, low organ specificity, pre-existing humoral immunity, and vector dose-dependent toxicity. In the present review, we address the different approaches to optimize AAV vector delivery system with focus on capsid engineering, packaging capacity, immune response at the clinical level. The review further investigates the potential of manipulating AAV vectors in preclinical applications and clinical translation, which emphasizes the challenges and prospects in viral vector selection, drug delivery strategies, immune reactions in cancer, neurodegenerative disease, retinal disease, SARS-CoV-2, and monkeypox. Finally, it forecasts future directions and potential challenges of artificial intelligence (AI), vaccine, and nanobody, which emphasizes the need for ethical and secure approaches in AAV application.

Background To investigate the phenotype and function of mucosal-associated invariant T (MAIT) cells in the peripheral blood of patients with Henoch-Schönlein purpura (HSP), owing to the lack of evidence on the role of MAIT cells in HSP. Methods Blood samples from patients with HSP and healthy donors (HDs) were assessed by flow cytometry and single-cell RNA sequencing (scRNA-seq) to analyze the proportion, phenotype, and function of MAIT cells. We analyzed Th-cytokines in the serum of patients with HSP by cytometric bead array (CBA). IgA in cocultured supernatant was detected by CBA to analyze antibody production by B cells. Results We found that the percentage of MAIT cells in patients with HSP was significantly reduced compared with that in HDs. HSP MAIT cells displayed activation phenotype with up-regulated CD69, FOS, and JUN, indicating that these cells were in the early stage of development. HSP MAIT cells also displayed a Th2-like profile with the capacity to produce interleukin (IL)-4 and IL-5. We also demonstrated that IL-4 was correlated with IgA levels in the serum of patients with HSP. Additionally, CD40L was up-regulated in HSP MAIT cells, and CD40L+ MAIT cells showed an enhanced ability to produce IL-4, leading to IgA secretion in patients with HSP. Conclusion Our data demonstrate that MAIT cells in patients with HSP exhibit an activated phenotype. The IL-4 production of CD40L+ MAIT cells in patients with HSP could take part in the pathogenesis of HSP and this finding suggested that targeting MAIT cells may constitute an attractive strategy for HSP.