Beyond electrical stimulation: toward neurotransmitter-mediated synaptic prostheses

Abstract Synaptic dysfunction and neurotransmitter imbalances are central to the pathogenesis of numerous neurological disorders. Conventional systemic pharmacological treatments often lack spatiotemporal precision, while traditional electrical stimulation is fundamentally limited by chronic gliosis and its reliance on intact synaptic machinery. To overcome these barriers, neurotransmitter-mediated synaptic prostheses, also called artificial synapses, have emerged as a promising bioelectronic alternative. This perspective provides the conceptual framework and recent technological advancements in the design of artificial synapses, ranging from stimulus-responsive nanocarriers and microfluidic platforms to advanced organic electronic ion pumps and closed-loop neuromorphic architectures. Despite significant engineering milestones, the clinical translation of these devices still faces biological and surgical challenges. We critically evaluate current limitations, highlighting the challenge of mechanical implantation trauma, off-target diffusion effects in dense neural tissue, and the constraints of a finite neurotransmitter reservoir. Furthermore, we explore pragmatic transitional solutions, such as subcutaneous refill ports, while discussing the feasibility and profound immunological risks associated with future in situ neurotransmitter synthesis. Ultimately, we highlight that bridging the gap between materials science and neurosurgical reality is essential for the successful clinical realization of next-generation adaptive biohybrid interfaces.