Precision Drug Delivery Strategies for Treatment-Resistant Depression: Opportunities and Challenges of FUS-BBBO and Spatial Molecular Profiling.

In this review, treatment-resistant depression (TRD),a clinically defined subtype of major depressive disorder, is characterized by substantial disease burden and heterogeneous pathophysiology, with many patients showing inadequate or transient responses to currently available pharmacological therapies. Emerging evidence indicates that some treatment failures may reflect limitations in central nervous system (CNS) drug delivery in addition to disease heterogeneity and pharmacological factors. TRD treatment failure from a drug-delivery perspective is reviewed here, and barriers such as the problem of crossing the blood-brain barrier, mismatch in drug distribution, and insufficient local PK/PD or target binding are listed. Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) is expected to be a method for targeted drug delivery to a specific area in the brain at a particular time, and it is not a standalone treatment for depression. FUS-BBBO has shown some preliminary clinical feasibility and safety in several CNS disorders, including neuro-oncology and neurodegenerative diseases, and is expected to be used as a new type of CNS drug delivery system. However, its application in TRD is still in the theoretical stage and requires disease-specific validation. To address target heterogeneity, spatial transcriptomics and single-nucleus multi-omics have been proposed in the review as necessary ways to optimise target selection. The above ways can increase the precision of the target Area by providing cell-type and molecular-level information that is unavailable in traditional imaging-based localisation methods, thereby improving the precision of therapeutic targeting. The medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hippocampus, and amygdala are potential target areas. Each connected to specific disease mechanisms and necessitating unique therapeutic agents. Finally, the review proposes a three-step translational framework-patient stratification, target constraint, and cargo matching-and delineates five interlinked clinical development barriers: long-term safety of repeated BBB opening, technical standardization and reproducibility, quantifiable intracerebral PK, biological hit verification, and mechanism-enriched trial design. We propose that the translational potential of FUS-BBBO in TRD may be realized through a closed-loop precision-therapy framework. This framework integrates patient stratification, region-specific delivery, pharmacodynamic verification, and mechanism-matched cargo selection.