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Updated: Jun 13, 2025
Intranasal Administration of CNS Therapeutics to Awake Mice
Published on: April 8, 2013
Nasal-to-brain delivery of CCR5 antagonist for reshaping the dysregulated microglia-neuron axis and enhancing
Pengcheng Zhang1, Yaxin Wang1, Yigang Xu2
1Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100070, China.
Abstract:
The dysregulation of the microglia-neuron axis plays a pivotal role in the pathogenesis of cognitive dysfunction following traumatic brain injury (TBI). The C-C chemokine receptor 5 (CCR5), markedly upregulated on both microglia and neurons post-injury, serves as a crucial mediator in the neuroinflammatory response and consequent neurological deficits. However, the therapeutic application of CCR5 antagonists in TBI is impeded by the delivery barriers presented by the blood-brain barrier (BBB) and their limited neuron-targeting efficacy. In this study, we introduce a novel nasal-to-brain delivery nanoplatform designed to facilitate the efficient brain delivery of DAPTA, a peptide antagonist of CCR5, aiming to inhibit CCR5 signaling and improving cognitive function following TBI. Biocompatible chitosan nanocarriers grafted with cell-penetrating peptide (TAT) and neuron-binding lactoferrin (Lf) were initially fabricated, demonstrating substantial DAPTA loading capacity, active mucosal and neural transportation, and enhanced neuron-targeting capabilities. The dual-engineered nanodrugs (DA@LT NPs) effectively penetrated the trigeminal and olfactory nerves, significantly enhancing the transport of DAPTA into the brain following intranasal delivery. In a TBI-induced mouse model, DA@LT NPs markedly alleviated the neuroinflammatory response, promoted M2 microglia polarization, protected neurons from pyroptosis, and improved both motor and cognitive functions of animals. The non-invasive intranasal delivery of the therapeutic CCR5 peptide antagonist using these mucus-penetrating and neuron-targeting nanoformulations presents a promising intervention for ameliorating neurological inflammation and cognitive impairments associated with TBI.
Insights
A novel nanoplatform delivers a CCR5 antagonist via the nose to the brain, effectively reducing neuroinflammation and improving cognitive function after traumatic brain injury (TBI). This approach overcomes blood-brain barrier challenges for TBI treatment.
Area of Science:
- Neuroscience
- Biomaterials Science
- Pharmacology
Background:
- Traumatic brain injury (TBI) causes cognitive dysfunction through microglia-neuron axis dysregulation.
- C-C chemokine receptor 5 (CCR5) is upregulated post-TBI, mediating neuroinflammation and deficits.
- Existing CCR5 antagonists face blood-brain barrier (BBB) and neuron-targeting delivery challenges.
Purpose of the Study:
- To develop a novel nasal-to-brain nanodelivery system for DAPTA, a CCR5 antagonist.
- To enhance brain delivery of DAPTA for inhibiting CCR5 signaling and improving TBI outcomes.
- To evaluate the efficacy of dual-engineered nanodrugs (DA@LT NPs) in a TBI mouse model.
Main Methods:
- Fabrication of chitosan nanocarriers grafted with cell-penetrating peptide (TAT) and lactoferrin (Lf).
- Intranasal administration of dual-engineered nanodrugs (DA@LT NPs) in a TBI mouse model.
- Assessment of neuroinflammation, microglia polarization, neuronal pyroptosis, and motor/cognitive functions.
Main Results:
- DA@LT NPs demonstrated high DAPTA loading, active mucosal/neural transport, and enhanced neuron targeting.
- Nanodrugs effectively utilized trigeminal and olfactory nerves for enhanced brain transport.
- Treatment significantly reduced neuroinflammation, promoted M2 microglia polarization, protected neurons, and improved cognitive and motor functions in TBI mice.
Conclusions:
- Non-invasive intranasal delivery of CCR5 antagonist via mucus-penetrating, neuron-targeting nanoformulations is effective.
- This approach offers a promising intervention for neurological inflammation and cognitive impairments post-TBI.
- The developed nanoplatform overcomes BBB limitations for TBI therapeutics.
