CN-122005851-A - Vagus nerve double-targeting delivery vehicle and preparation method and application thereof

Abstract

The invention discloses a vagus nerve double-targeting delivery vehicle and a preparation method and application thereof. The vagus nerve double-targeting delivery vehicle is characterized in that a first targeting ligand capable of being respectively combined with nicotinic acetylcholine receptors on the surface of vagus nerve neurons and a second targeting ligand capable of being specifically combined with transient receptor potential channels are simultaneously modified on the surface of a nano-carrier. According to the invention, through a lymphatic path guiding and dual-receptor molecule recognition targeted delivery strategy, the enrichment efficiency and the spatial selectivity of the photoresponsive nano-carrier in the vagus nerve region are effectively improved, the specific targeting of the photoresponsive nano-carrier to the vagus nerve is enhanced, the effective activation of the vagus nerve can be realized under lower optical power density in the subsequent NIR light irradiation process, the non-specific stimulation to surrounding non-target tissues is obviously reduced, and the safety and the accuracy of the optical regulation of the vagus nerve are improved.

Inventors

• CHEN GUANGCUN
• Yuan Qinhui
• YIN HONGQIANG
• WANG QIANGBIN
• WANG TAO

Assignees

• 中国科学院苏州纳米技术与纳米仿生研究所

Dates

Publication Date

20260512

Application Date

20260302

Claims (10)

1. 1. The vagus nerve double-targeting delivery vehicle is characterized in that the surface of the nano-carrier is modified with a first targeting ligand capable of being specifically combined with nicotinic acetylcholine receptors on the surface of vagus nerve neurons and a second targeting ligand capable of being specifically combined with transient receptor potential channels.
2. 2. The vagal dual targeting delivery vehicle according to claim 1, wherein the nanocarrier comprises a material with NIR light response capability, preferably the material with NIR light response capability comprises any one or more of indocyanine green, gold nanomaterial, conjugated polymer nanoparticles, polydopamine nanoparticles, quantum dots or BODIPY type dyes.
3. 3. The vagal dual targeted delivery vehicle of claim 1, wherein the first targeting ligand is selected from a choline analog, a nAChR specific peptide fragment, or a derivative thereof.
4. 4. The vagal dual targeted delivery vehicle of claim 1, wherein the second targeting ligand is selected from the group consisting of capsaicin analogs, TRP binding peptides, or derivatives thereof.
5. 5. The vagal dual targeted delivery vehicle of claim 1, wherein the first targeting ligand and the second targeting ligand are each covalently linked to the nanocarrier surface by a flexible linking arm, preferably a polyethylene glycol segment.
6. 6. The vagal dual-targeting delivery vehicle of claim 5, wherein the first targeting ligand is covalently linked to the surface of the pegylated nanoparticle by amidation, click chemistry or thiol-maleimide reaction, and the second targeting ligand is linked to the same nanoparticle surface by different reactive sites or sequential coupling without affecting the activity of the first targeting ligand, thereby forming a dual-targeting modified structure.
7. 7. The vagal dual targeting delivery vehicle according to claim 4, wherein the particle size of the dual targeting delivery vehicle is 30-200 nm, preferably 50-120 nm.
8. 8. The method for preparing the vagus nerve dual-targeting delivery vehicle according to any one of claims 1 to 7, which is characterized by comprising the step of coupling a nanocarrier with a first targeting ligand and a second targeting ligand of a vagus nerve surface receptor to prepare the vagus nerve dual-targeting nanocarrier.
9. 9. Use of the vagal dual targeting delivery vehicle according to any of claims 1 to 7 for the manufacture of a medicament for the treatment of a vagal-related disorder.
10. 10. The use according to claim 9, wherein the disease comprises epilepsy, heart failure, inflammation or other metabolic disorders.

Description

Vagus nerve double-targeting delivery vehicle and preparation method and application thereof Technical Field The invention relates to the technical field of biomedicine, in particular to a vagus nerve double-targeting delivery vehicle and a preparation method and application thereof. Background Epilepsy is a chronic brain disease caused by a variety of etiologies and is characterized by sudden central nervous system dysfunction caused by overdischarge of brain neurons. Vagal nerve stimulation is one of the current common and effective epileptic interventions, and vagal nerve stimulation can reduce the intensity and duration of seizures and post-seizure symptoms through the effects of desynchronization of neuronal activity, hippocampal plasticity, anti-inflammatory and neurotransmitter release modulation, and the like. The vagus nerve is the longest and most widely distributed brain nerve of a human body, is an important information channel connecting a central nervous system and peripheral organs, and plays a key role in various physiological processes such as heart rate regulation, gastrointestinal peristalsis, immunoinflammatory reflex, endocrine metabolism regulation and the like. Clinical studies have shown that vagal nerve dysfunction is closely related to a variety of major diseases such as epilepsy, depression, heart failure, rheumatoid arthritis, obesity, diabetes and the like. Currently, vagal nerve stimulation (Vagus Nerve Stimulation, VNS) has become an effective means for treating diseases such as drug-resistant epilepsy, depression, and rheumatoid arthritis. The traditional VNS mainly adopts an implanted electrode to electrically stimulate the cervical vagus nerve, and although the mode has been approved by the FDA for treating refractory epilepsy and depression, the mode still has the obvious limitations of high invasiveness, limited space selectivity, easy initiation of side reaction, and the risks of infection, displacement, electrode aging and the like when the electrode is implanted for a long time. In recent years, non-invasive nerve regulation modes such as magnetic stimulation, low-intensity focused ultrasound and the like are continuously developed and used for realizing vagus nerve stimulation. The magnetic stimulation relies on electromagnetic induction, so that percutaneous nerve regulation and control can be realized, but the focusing capability on small-scale peripheral nerves is still limited, and the low-intensity focused ultrasonic energy can realize deep and non-invasive regulation and control, but the stimulation parameter optimization and the action mechanism are still explored. The technology reduces the invasiveness to a certain extent, but the problems that the targeting selectivity is insufficient, the action range is difficult to accurately limit and the like are still common. Near-Infrared (NIR) has the advantages of deep tissue penetration, fine controllability, high spatial resolution and the like, and provides a new technical path for realizing high-selectivity regulation and control of nerves. With the development of material science and optical technology, neuromodulation strategies based on photoresponsive functional materials are also receiving increasing attention. In vagal nerve regulation, if a material with optical response characteristics can be introduced and effective enrichment or orientation of the material in a vagal nerve region is realized, the spatial precision and safety of regulation are expected to be obviously improved. Under NIR light irradiation, the functional material can convert light energy into photo-thermal, photoelectric or opto-mechanical effect locally, and can regulate nerve excitability, action potential release frequency and signal transmission without contacting nerve and depending on traditional electrode. Compared with an electric, magnetic or ultrasonic stimulation mode, the vagus nerve regulation mode based on combination of the NIR light and the NIR light response material has the advantages of high spatial resolution, mild stimulation mode, low tissue damage risk and the like. In view of the above, a material capable of achieving accurate targeting to the vagus nerve and effective regulation and control under the action of NIR light and an application method thereof are needed to overcome the problems of high invasiveness, poor targeting and the like in the existing vagus nerve stimulation technology. The invention is put forward under the background, aims to provide a vagus nerve double-targeting delivery vehicle and application thereof in nerve light regulation, and is not only hopeful to break through the limitation of the existing vagus nerve stimulation means, but also provides a new tool and technical direction for intervention and research of related diseases caused by vagus nerve dysfunction. However, even if dual targeting delivery vehicles can be prepared based on the prior art, further research is needed for the s