Intranasal biomaterials for treatment-resistant depression: device-formulation coupling and therapeutic exposure

Treatment-resistant depression (TRD) is commonly defined as depression that does not achieve an adequate response or remission after at least two antidepressant treatments of adequate dose and duration during the current depressive episode, although exact criteria vary across studies. Intranasal delivery is attracting renewed interest in TRD because it enables rapid administration, avoids gastrointestinal degradation and first-pass metabolism, and may support direct or indirect access to the central nervous system. However, clinical translation cannot be established by particle size, drug loading, or behavioral efficacy alone. A viable intranasal biomaterial-device product must generate reproducible therapeutic exposure through a coupled formulation-device-anatomy system, in which material properties shape spray performance, regional deposition, mucosal residence, epithelial transport, pharmacokinetics, safety, and therapeutic response. This Perspective examines how polymer composition, surface chemistry, particle mechanics, gelation, viscosity, and release kinetics interact with metered-dose devices, spray plume characteristics, nasal anatomy, and mucociliary clearance. Particular attention is given to the distinction between nasal deposition and brain delivery, the need for quantitative pharmacokinetic and biodistribution evidence, and the local safety requirements of repeated administration to respiratory and olfactory epithelia. We also propose indication-specific outcome standards for treatment-resistant depression that extend beyond short-term behavioral tests or isolated symptom scores to include onset, durability, cognition, sleep, daily function, adherence, and treatment burden. Artificial intelligence, medical-image-based airflow simulation, three-dimensional nasal models, and digital outcome measures may strengthen selected steps of this development pathway, but they should support rather than replace experimental validation. The central position of this article is that intranasal biomaterial-device products for treatment-resistant depression should be judged by reproducible, clinically relevant exposure with an acceptable benefit-risk profile, rather than by material sophistication alone.