Recombinant adeno-associated viruses (rAAVs) have emerged as an attractive tool for gene delivery, and demonstrated tremendous promise in gene therapy and gene editing—therapeutic modalities with potential “one-and-done” treatment benefits compared to conventional drugs. Given their tropisms for the central nervous system (CNS) across various species including humans, rAAVs have been extensively investigated in both pre-clinical and clinical studies targeting neurodegenerative disease. However, major challenges remain in the application of rAAVs for CNS gene therapy, such as suboptimal vector design, low CNS transduction efficiency and specificity, and therapy-induced immunotoxicity. Therefore, continuing efforts are being made to optimize the rAAV vectors from their “core” genetic payloads to their “coat” or capsid structure. In this review, we describe current approaches for rAAV vector design tailored for transgene expression in the CNS, summarize the development of CNS-targeting AAV serotypes, and highlight recent advancements in AAV capsid engineering, aimed at generating a new generation of rAAVs with improved CNS tropism. Additionally, we discuss various administration routes for delivering rAAVs to the CNS and provide an overview of AAV-mediated gene therapies currently under investigation in clinical trials for the treatment of neurodegenerative diseases.

Visual impairment, stemming from genetic, degenerative, and traumatic causes, affects millions globally. Recent advancements in ophthalmology present novel strategies for managing and potentially reversing these conditions. Here, we explore 10 emerging avenues—including gene therapy, stem cell therapy, advanced imaging, novel therapeutics, nanotechnology, artificial intelligence (AI) and machine learning, teleophthalmology, optogenetics, bionics, and neuro-ophthalmology—all making strides to improve diagnosis, treatment, and vision restoration. Among these, gene therapy and stem cell therapy are revolutionizing the treatment of retinal degenerative diseases, while advanced imaging technologies enable early detection and personalized care. Therapeutic advancements like anti-vascular endothelial growth factor therapies and neuroprotective agents, along with nanotechnology, have improved clinical outcomes for multiple ocular conditions. AI, especially machine learning, is enhancing diagnostic accuracy, facilitating early detection, and personalized treatment strategies, particularly when integrated with advanced imaging technologies. Teleophthalmology, further strengthened by AI, is expanding access to care, particularly in underserved regions, whereas emerging technologies like optogenetics, bionics, and neuro-ophthalmology offer new hope for patients with severe vision impairment. In light of ongoing research, we summarize the current clinical landscape and the potential advantages of these innovations to revolutionize the management of visual impairments. Additionally, we address the challenges and limitations associated with these emerging avenues in ophthalmology, providing insights into their future trajectories in clinical practice. Continued advancements in these fields promise to reshape the landscape of ophthalmic care, ultimately improving the quality of life for individuals with visual impairments.

Objective: Dendritic cells (DCs) play a pivotal role in orchestrating anti-tumor immune responses. However, various factors can suppress DCs function and compromise anti-tumor immunity. Itaconate, a metabolite activated during inflammation and infection, has been identified to possess immunomodulatory properties, but its role on DCs remains largely unexplored. In this study, we aimed to investigate the role of itaconate in regulating the maturation and function of DCs and its underlying molecular mechanism. Methods: Bone marrow-derived dendritic cells (BMDCs) were treated with 4-octyl itaconate (4OI). The expression levels of CD40, CD80, CD86, and MHC-II on BMDCs were analyzed by flow cytometry. The mRNA expression of cytokines was assessed using RT-qPCR. BMDCs with different treatment were adoptively transferred to B16-OVA tumor-bearing mice. The production of IFN-γ, IL-2, and TNF-α in CD4⁺ T and CD8⁺ T cells were analyzed by flow cytometry. The protein level of NRF2 in BMDCs was analyzed by Western blot. Results: Treatment with 4OI represses DC maturation and function. Specifically, 4OI-treated DCs exhibited impaired phenotypic and functional maturation, characterized by decreased expression of co-stimulatory molecules CD40, CD80, and CD86, as well as lower levels of pro-inflammatory cytokines IL-12, IL-6, TNF-α and IL-1β. Furthermore, these DCs demonstrated a diminished capacity to stimulate T cell responses both in vitro and in vivo. Mechanistically, 4OI inhibits DCs maturation and function through enhancing and activating KEAP1/NRF2 pathway. Conclusion: This study reveals that 4OI inhibits DC function through NRF2 activation, elucidating the immunomodulatory mechanisms of itaconate and emphasizing its pivotal role in developing targeted DC-based tumor immunotherapy strategies.