Advancements in Nanotherapeutics for the Treatment of Depression via Intranasal Pathway: A Review

Abstract

Depression is a complex psychiatric disorder marked by persistent emotional disturbances such as sadness, hopelessness, and fatigue, frequently accompanied by psychosocial impairments. Current treatment approaches are hindered by limited efficacy, poor patient adherence, and the inability of many therapeutic agents to effectively penetrate the blood-brain barrier (BBB). The BBB, a selective and protective interface between the bloodstream and brain tissue, restricts drug delivery to the central nervous system (CNS), resulting in suboptimal concentrations of antidepressants at the target site and delayed therapeutic responses. This review explores the limitations of conventional drug delivery systems for depression and highlights the intranasal route as a promising non-invasive alternative for direct brain targeting. Intranasal delivery bypasses hepatic first-pass metabolism and systemic degradation, offering rapid drug absorption and CNS access through olfactory and trigeminal neural pathways. Among emerging strategies, nanotherapeutics have gained increasing attention due to their capacity to improve solubility, protect labile compounds, and provide sustained drug release. Nanoparticles can encapsulate both hydrophilic and lipophilic drugs, enhancing their pharmacokinetics and stability. When administered intranasally, these nanocarriers can directly reach the brain, potentially reducing dosage frequency and enhancing therapeutic outcomes, while minimizing systemic side effects. This review focuses on the latest advancements in intranasal nanotherapeutic formulations for depression, such as polymeric nanoparticles, nanoemulsions, solid lipid nanoparticles, and nanostructured lipid carriers. The synergistic integration of nanotechnology and targeted CNS delivery offers a transformative approach to overcome the challenges posed by the BBB and improve depression management. While preclinical findings are promising, further clinical studies are necessary to confirm safety, efficacy, and long-term outcomes. Overall, intranasal nanotherapeutics represent a compelling direction for the development of next-generation antidepressant therapies, aiming to achieve faster onset, improved adherence, and enhanced quality of life for patients suffering from depression.

Keywords: blood brain barrier; depression; intranasal; nanocarriers; nanotherapeutics.

Figure 1

Restoration of neurotransmitter levels through nanotherapeutic delivery.

Figure 2

Schematic representation of nasal regions and drug absorption pathways across the olfactory epithelium.

Figure 3

Types of nanotherapeutic agents used to treat depression.

Figure 4

CLSM images of brain at 30 min after intranasal administration of ROD-123 tagging buspirone -SLNs (A); ROD-123 Sol (B). Reproduced from Yasir M, Chauhan I, Zafar A, et al. Buspirone loaded solid lipid nanoparticles for amplification of nose to brain efficacy: formulation development, optimization by Box-Behnken design, in-vitro characterization and in-vivo biological evaluation. J Drug Delivery Sci Technol. 2021;61:102164.chi. © 2020 Elsevier B.V. All rights reserved.