Abstract Intranasal administration, as a non-invasive brain-targeted delivery strategy, offers a promising approach for the treatment of central nervous system disorders, particularly depression. Traditional oral or intravenous drug delivery is often limited by the restrictive permeability of the blood-brain barrier and the hepatic first-pass effect, which hinder effective drug accumulation in the brain. In contrast, the intranasal route leverages the olfactory and trigeminal neural pathways to enable direct drug transport from the nasal cavity to the brain, effectively bypassing the blood-brain barrier and significantly enhancing brain drug bioavailability. This article systematically reviews the research progress of intranasal drug delivery in the treatment of depression-like behaviors, highlighting the technological evolution of various drug-loading modalities, including solutions, gels, nanoparticles, in situ gels, and cell membrane biomimetic carriers, and analyzes their differences in nasal mucosal retention time, mucus penetration ability, and brain-targeting efficiency. Furthermore, it elaborates on the multiple antidepressant mechanisms of intranasal materials, such as regulating neurotransmitter systems (e.g., 5-Hydroxytryptamine, Dopamine, Glutamate), inhibiting neuroinflammation (e.g., microglial activation, inflammatory factor release), enhancing neuroplasticity (e.g., promoting hippocampal neurogenesis and synapse formation), and modulating the gut microbiota-gut-brain axis. Simultaneously, the article integrates data from multiple clinical trials, focusing on evaluating the efficacy and safety of intranasal formulations such as esketamine in treatment-resistant depression, highlighting their advantages of rapid onset and high response rates, and discussing management strategies for adverse reactions such as dose individualization, local irritation, and dissociative symptoms. Addressing current technical bottlenecks, such as uneven drug absorption due to nasal physiological differences, challenges in the large-scale production of nanocarriers, and insufficient long-term safety evidence, the article proposes that future research should focus on the development of intelligent responsive nanocarriers, the construction of multimodal synergistic treatment systems, the design of personalized medication regimens guided by precision medicine, and the coordinated advancement of real-world research and regulatory standards. This review aims to provide comprehensive theoretical support and development directions for the clinical translation of intranasal drug delivery in the field of depression treatment. Graphical abstract
An et al. (Wed,) studied this question.