Citation: Tianshu Zhang, Xiaodong Li, Yinghua Peng, Cong Lin, Xiaohui Wang. Intranasal delivery of cannabidiol-loaded hypoxic exosomes for targeted treatment of methamphetamine addiction via enhanced brain penetration and neuroinflammation modulation[J]. Chinese Chemical Letters, ;2026, 37(8): 111794. doi: 10.1016/j.cclet.2025.111794 shu

Intranasal delivery of cannabidiol-loaded hypoxic exosomes for targeted treatment of methamphetamine addiction via enhanced brain penetration and neuroinflammation modulation

Tianshu Zhang ^{a, b} ,
Xiaodong Li ^c ,
Yinghua Peng ^{d, *,} ,
Cong Lin ^{b, *,} ,
Xiaohui Wang ^{a, b, *,}

a.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China
b.
Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
c.
Shenzhen Sciencare Drug Research Institute, Shenzhen 518118, China
d.
Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130112, China

pengyinghua@caas.cn

cong.lin@ciac.ac.cn

xiaohui.wang@ciac.ac.cn

Received Date: 14 June 2025
Revised Date: 29 August 2025
Accepted Date: 5 September 2025
Available Online: 5 September 2025

Figures(4)

Methamphetamine (METH) addiction represents a severe global public health crisis with currently limited therapeutic options, highlighting an urgent need for innovative approaches. Emerging evidence indicates that neuroinflammation, particularly microglial activation and subsequent cytokine release, significantly contributes to the neuropathology associated with METH use. Cannabidiol (CBD), a phytocannabinoid with promising anti-inflammatory and neuroprotective properties, has demonstrated therapeutic potential in mitigating METH-related neuroimmune responses. However, its clinical translation is severely restricted due to low bioavailability, rapid hepatic metabolism, and limited blood-brain barrier (BBB) penetration. To address these challenges, we developed a novel therapeutic platform utilizing exosomes derived from hypoxia-preconditioned human umbilical vein endothelial cells. These exosomes were loaded with CBD and surface-functionalized with the transcriptional activator protein (TAT) peptide, generating HP-Exo-CBD-TAT, to enhance brain targeting. Intranasal administration of HP-Exo-CBD-TAT significantly improved BBB penetration and brain accumulation compared to unmodified CBD-loaded exosomes (HP-Exo-CBD). In mouse models of METH addiction, treatment with HP-Exo-CBD-TAT markedly attenuated behavioral sensitization and conditioned place preference (CPP), two key indicators of addiction-like behaviors. The observed therapeutic effects correlated strongly with reductions in microglial activation and pro-inflammatory cytokine expression (interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α)) in critical addiction-associated brain regions, such as the medial prefrontal cortex and ventral tegmental area. Importantly, even the carrier alone (HP-Exo-TAT) exhibited intrinsic immunomodulatory effects, underscoring the dual therapeutic action of this delivery system. Our findings highlight HP-Exo-CBD-TAT as a highly efficient, biocompatible, and non-invasive strategy that effectively targets neuroinflammation and addictive behaviors. This intranasal exosomal platform demonstrates significant translational promise for the clinical management of METH addiction.
- Methamphetamine addiction,
- Cannabidiol (CBD),
- Neuroinflammation,
- Exosome drug delivery,
- Intranasal administration
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