Introduction

Depression is a widespread and potentially life-threatening neurological disorder that has garnered attention from researchers around the world. It not only has psychological manifestations involving emotions and cognition but also manifests neurological damage, such as decreased volition and cognitive impairment, and even physical symptoms, such as autonomic nervous system dysfunction. Moreover, depression often co-occurs with other psychiatric disorders, such as posttraumatic stress disorder, anxiety disorders, obsessive–compulsive disorder, and substance use disorders, and comorbidities, such as cardiovascular disease, diabetes, stroke, and cancer, frequently occur [1]. Depression has become a highly concerning public health issue on an international scale. However, due to the complex pathological mechanisms of neurological diseases, frontline health care professionals often face clinical difficulties such as complex adverse reactions and low treatment efficacy. As a result, scientists have started contemplating multiple possible treatment strategies. The combination of natural medicines and novel drug delivery systems (NDDSs) has entered our vision.

The attributes of natural medicines, possessing mechanisms of action that can intervene in multiple disease targets and pathways, have stimulated considerable interest among researchers in natural drug antidepressant therapies. Natural medications have the characteristics of fewer adverse reactions, significant therapeutic effects, and the ability to function in synergy with multiple components. Compared to traditional synthesized small-molecule drugs, natural drugs also have the advantages of abundant resources, low cost, and easy availability, making them an important source of new drug development. More than half of the new chemical entity drugs developed internationally are directly or indirectly derived from natural medications. Natural medications have enormous medical value and market potential.

The vigorous development of science and technology has brought breakthroughs in medical technology. The updating of the research content and paradigm in the field of drug delivery systems has solved multiple problems in drug bioavailability and stability, providing more possibilities for the treatment of clinical nervous system disorders. The breakthroughs in drug delivery routes and delivery vehicle research in the drug delivery system field have improved the efficacy of drugs used to treat nervous system diseases. The emergence of NDDSs has shown new clinical prospects in the formulation research of drugs. The development and maturity of drug delivery technology have provided impetus for the clinical transformation of many new drugs.

With the development of pharmaceuticals and the high pursuit of efficacy, the medical community has conducted further development and research on the enhancement of the absorption efficiency of active ingredients in natural medicines through the application of NDDS technology, which has resulted in notable therapeutic outcomes. Mature scientific research methods, such as nanotechnology, have significantly propelled the development of natural medicinal plant antidepressant treatment practices. Therefore, this review discusses interventions in neurological disease research from the perspective of novel drug delivery systems and involves exploring natural medicinal plant antidepressant strategies. The information in this review provides a novel theoretical foundation for studying new delivery strategies of natural medicinal plant active ingredients in the field of psychiatric research.

Obstacles to traditional drug delivery methods and obstacles to BBB

Based on the evidence from modern medical systems, natural medicines encompass plant-, animal-, and mineral-derived drugs that possess pharmacological effects. Among these, plant-based medicines predominate in natural medicine, whereas animal, mineral, and other forms of natural medicines are used to a relatively lesser extent. Over time, various applied systematic theories have evolved in the field of natural medicine, including Chinese medicine, Indian Buddhist medicine, Islamic medicine, European traditional herbal medicine, South American ethnomedicine, and African ethnomedicine.

The study of nervous system diseases in traditional Chinese medicine (TCM) has a long history; as early as the Shang and Zhou Dynasties in ancient China, there were records about brain disorders in oracle bone inscriptions, such as ‘King Wu was diagnosed due to headaches’ [2]. ‘Huang Di Nei **’ also contains numerous discussions on brain disorders [3, 158]. The intranasal administration of Panax ginseng saponin was found to significantly alleviate cerebral oedema and stroke symptoms resulting from cerebral ischaemia‒reperfusion in gerbils, while administering the same dose of an oral solution had minimal effect [159].

Ototopical administration

The 'Inner Canon of the Yellow Emperor' (the most authoritative text of early medical theory and drug therapy), a classical text on Chinese medicine, associates the ear with the brain and suggests that damage to the brain can result in damage to the ear [160]. Furthermore, the Chinese medical text ‘Suwen-Xuanji-original disease Formula’ contains records of acupuncture and magnetic therapy being used to treat deafness. The traditional Chinese medicine approach to treating ear issues is a distinct and specialized technique within this field [161]. Based on Chinese medicine principles, the ear is interconnected with internal organs and meridians. Consequently, when medication is administered via the external ear canal, it can travel through the meridian and access the internal organs, successfully treating illnesses and even saving lives [162, 203]. The blood‒brain barrier is a highly specialized structure that limits the movement of compounds between the blood and brain tissue. This barrier is created by a unique arrangement of components, including the nonporous endothelium of the brain capillaries, a continuous and unbroken basement membrane, and the perivascular astrocytic foot processes. These components possess varied permeability to different substances, which contributes to the selective transport of molecules into the brain [].

Modulating BBB permeability is a microenvironmental modification strategy aimed at selectively enhancing or restricting the passage of substances. The permeability of the blood‒brain barrier is primarily dictated by the integrity of the tight junctions between cerebral vascular endothelial cells, as well as the activity of efflux transporters such as P-glycoprotein (P-gp). Other factors, such as intercellular gaps, endocytosis, and transcytosis, also play a role in regulating BBB permeability [204]. Due to their fat solubility and aromatic properties, certain Kaigiao herbs, such as musk, borneol, and Acorus calamus, are able to readily cross the blood‒brain barrier. These herbs have been shown to inhibit the efflux of P-gp, resulting in increased drug concentrations within the brain. Additionally, these herbs have been found to suppress the expression of the protein Claudin-5, which widens the tight junctions between vascular endothelial cells, thereby enhancing BBB permeability. Acorus tatarinowii and borneol also increase the content of 5-hydroxy tryptamine (5-HT) and receptor binding rates, promoting the opening of tight junctions via endothelial cell contraction and increasing BBB permeability. Furthermore, Storesin and benzoin have been shown to increase BBB permeability by modulating P-gp exocytosis [168, 205]. Under pathological conditions, musk, borneol, Storesin, and benzoin have been found to reduce the content of inflammatory factors, which slows the damage of tight junctions between endothelial cells. Musk has also been shown to inhibit matrix metalloproteinase expression and mitigate cell damage caused by free radicals, promoting increased stability and reducing the permeability of the BBB and protecting brain tissues. Acorus calamus is capable of reducing BBB permeability through its anti-free radical properties, protecting brain tissues [206]. Cai Wei**’s study explored the effects of sodium hesperidin on the sarcoma homologue A (RhoA)/Rho-associated coiled-coil protein kinase (ROCK) pathway and BBB permeability in rats with bacterial meningitis (BM). The study demonstrated that sodium aescinate (SA) was able to improve brain oedema and BBB permeability in rats with BM. These beneficial effects of SA on BBB damage may be attributed to the inhibition of Rohan/ROCK pathway activation [207].

Concluding remarks and future perspective

In recent years, there has been a gradual increase in the incidence of depression. However, due to the unique structural characteristics of the BBB in neurological disorders, active drug molecules are unable to accumulate in brain lesions, severely impacting the effectiveness of treatment. Therefore, the search for novel and efficient drugs to treat brain diseases has become an urgent matter in today’s society. Domestic and international research has demonstrated that certain new drug delivery systems are capable of partially overcoming the BBB limitations and delivering drugs to focal areas in the brain, thus improving therapeutic effectiveness. The research and development of new systems have become a focus of clinical development. The aim of novel drug delivery systems, such as nanomedicines, liposomes, microneedles, and subcutaneous injections, is to improve drug efficacy and reduce side effects while enhancing patient compliance. These systems have advantages in terms of drug delivery, enhanced drug efficacy, controlled drug release, and other aspects and have achieved certain results in clinical development (Table 5).

Table 5 Novel drug delivery systems in clinical development
Full size table

NDDSs are the foundation of drug formulation research and play a pivotal role in the development of the global pharmaceutical industry. The focus of NDDS research is to optimize drug efficacy and reduce unwanted side effects by implementing three fundamental strategies: targeting space, release time, and dose. The scope of NDDSs encompasses various objectives, such as controlled drug release, drug targeting, enhanced drug stability, the regulation of drug metabolism time, improved drug absorption, and overcoming biological barriers.

The cornerstone of modernizing Chinese medicine lies in the modernization of Chinese medicine formulations. By harnessing the advantages of traditional Chinese medicine in treating brain diseases and integrating modern new drug delivery systems, Chinese medicine can effectively treat brain diseases and the dosage forms of Chinese medicines can be improved. The key factors affecting the ability of a drug to cross the BBB include its lipid solubility, molecular weight, and dissociated or nondissociated form under physiological conditions. NDDSs have demonstrated the ability to enhance the ability of Chinese medicines to penetrate the BBB and increase drug concentrations in the brain. This combination of strengths minimizes the adverse effects of Chinese medicines while maximizing their therapeutic benefits.

In conclusion, the vast potential of Chinese medicine remains largely untapped. Outdated drug delivery methods have limited the efficacy of Chinese medicines. The application of new drug delivery technologies to Chinese herbal medicines will undoubtedly help to enhance the therapeutic efficacy of various Chinese medicinal compounds and herbs while reducing the side effects of drugs. The progress made by modern science has provided additional opportunities to explore the benefits of Chinese medicine. While new drug delivery systems have shown promise in treating brain diseases, they are still in their early stages, and numerous challenges are encountered. Further research is necessary to refine drug delivery carriers and optimize TCM formulations.