MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and serve as cancer biomarkers. Studies show that miR-148a suppression is linked to metastasis in various tumors and upregulation of metastasis-related genes (41). Transforming growth factor-β (TGF-β) plays an important role in tissue and organ development, as well as cell proliferation, differentiation, and apoptosis. It can affect epithelial and endothelial cell differentiation, increase immune cell recruitment, and is an important cytokine involved in the activation of cancerous mesenchyme (42). Small mothers against decapentaplegic (SMAD) proteins are key proteins that conduct TGF-β signaling from cell surface receptors to the nucleus (43).

Jiang et al. found that glabridin significantly inhibited the adhesion-dependent growth and sphere formation of HepG2 and MHCC97H hepatocellular carcinoma cells (44). It increased miR-148a expression in a dose- and time-dependent manner, targeting TGF-β and SMAD protein activation, and reducing tumor cell invasion and metastasis. Another study showed that glabridin reduced miR-148a methylation and upregulated its expression in breast cancer cells, inhibiting the TGF-β/SMAD pathway and suppressing metastasis (34).

miR-148a significantly inhibits tumor cell invasion and metastasis by targeting the TGF-β/SMAD signaling pathway. However, the mechanisms of action of miR-148a across different cancer types have not been fully elucidated. miR-148a not only exerts its effects within cancer cells, but may also influence immune escape mechanisms by modulating immune responses in the tumor microenvironment (45). Whether glabridin can alter the tumor microenvironment by regulating miR-148a and thereby provide a new target for immunotherapy requires further investigation.

EMT is a crucial process involving the transformation of epithelial cells, which alters intercellular adhesion patterns and affects cell proliferation and differentiation. EMT is closely associated with embryonic development, tissue repair, and cancer progression (46). Aberrant activation of EMT is linked to malignant properties of tumor cells during cancer progression and metastasis, such as increased tumor cell migration and invasiveness, enhanced tumor stemness, and greater resistance to chemotherapy and immunotherapy (47). Therefore, targeting and blocking the EMT process is crucial for controlling tumor invasion and metastasis.

Glabridin inhibited the proliferation, migration, and invasion of lung adenocarcinoma cells A549 (35). Further studies revealed that glabridin decreased the expression of neural cadherin (N-cadherin) and vimentin, and upregulated the expression of epithelial cadherin (E-cadherin) in tumor cells. N-cadherin and vimentin are positively correlated with EMT and are considered its markers (48, 49), whereas E-cadherin acts as a tumor suppressor protein (50). Another study found that glabridin inhibited EMT in breast cancer cells by upregulating E-cadherin and occludin, while downregulating vimentin, E-box-binding zinc finger protein 1 (Zeb1), and other critical EMT markers, thereby exerting a controlling effect on tumor invasion and metastasis (36).

FAK is a key signaling molecule involved in cell adhesion, migration, proliferation, and survival. Its overactivation in various cancers makes it an important target for developing new anti-cancer therapies (51). Src is a non-receptor tyrosine kinase that phosphorylates tyrosine residues on proteins. Unlike receptor tyrosine kinases, Src is not membrane-bound and acts at various intracellular sites, affecting many cellular processes. Src is often overactive in cancers, leading to uncontrolled cell proliferation, increased invasion and metastasis, and resistance to apoptosis (52). FAK typically forms a complex with Src, jointly regulating cell growth, survival, and motility. Aberrant activation of FAK/Src signaling is frequently observed in aggressive tumors (53).

Glabridin was found to inhibit the invasion and metastasis of human non-small cell lung cancer A549 cells (54). Studies have shown that glabridin inhibits lung cancer cell invasion and metastasis by reducing FAK and Src activities, leading to FAK/Src complex inactivation. Additionally, glabridin can suppress the invasion, metastasis, and angiogenesis of breast cancer cells through the FAK/Src pathway (55), the specific mechanism is that glabridin inhibits the migration and invasion of cancer cells by reducing the phosphorylation of key proteins. It also regulates cytoskeleton reorganization to prevent cell movement by inhibiting the Ras homolog family member A(RhoA)/Rho-associated coiled-coil containing protein kinase (ROCK) signaling pathway and reducing the phosphorylation of myosin light chain (MLC). In addition, glabridin directly inhibits the migration and tube formation of vascular endothelial cells, thereby effectively inhibiting angiogenesis. These multi-pathway effects suggest that glabridin has a strong potential to inhibit breast cancer invasion and metastasis.

The FAK/Src signaling pathway plays a crucial role in tumor cell migration, invasion, and metastasis. Glabridin exerts anti-metastatic effects in various tumors by inhibiting the activation of the FAK/Src complex. Since FAK/Src also plays a key role in tumor angiogenesis (56), future research should focus on the inhibition of tumor angiogenesis by glabridin through its effect on FAK/Src, to assess its novel potential as a therapeutic strategy.

MMPs have been shown to play an important role in the abnormal proliferation, local invasion, and metastasis of tumor cells (57). They can degrade almost all protein components in the extracellular matrix (ECM), destroy the histological barrier to tumor cell invasion, and act as proteases that remodel the extracellular matrix, driving the cell invasion process (58).

Jie et al. (59) found that glabridin inhibits the invasion and migration of osteosarcoma cells. The specific mechanism involves down-regulating p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, which affects the binding of cyclic adenosine monophosphate response element-binding protein-associated protein 1 (CREB-AP1) to the promoters of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), thereby inhibiting tumor cell migration and invasion. Another study found that glabridin inhibits melanoma cell proliferation and migration by reducing MMP-2 activity and expression (60). In a study involving glabridin intervention in liver cancer cells Huh7 and Sk-Hep-1, the relationship between glabridin’s regulation of MMPs and the inhibition of tumor cell invasion and migration was further verified (61). The results showed that glabridin downregulated MMP-9 by interfering with nuclear factor-κB (NF-κB) and AP-1 binding activity, ultimately inhibiting tumor cell invasion and metastasis. For detailed information, please refer to Table 1.

Energy metabolism disorders are regarded as one of the hallmarks of cancer (64). In tumor tissues, glycolysis is the main metabolic pathway for adenosine triphosphate (ATP) production. Cancer cells depend on metabolic reprogramming and transition to a “glycolytic” metabolic phenotype to sustain the energy necessary for proliferation (65, 66). Hexokinase-2 (HK-2) is the primary rate-limiting enzyme in glycolysis and a key regulator in the glucose metabolic pathway. HK-2 catalyzes the phosphorylation of glucose to produce glucose-6-phosphate (G-6-P) (67). Lactate dehydrogenase (LDH) is a crucial enzyme in glycolysis. LDH exists in three isoforms: Lactate dehydrogenase A (LDHA), Lactate dehydrogenase B (LDHB), and Lactate dehydrogenase C (LDHC). Among these, LDHA is the predominant isoform in various malignant tumors, including colon cancer, ovarian cancer, gastric cancer, and lung cancer (68). LDH catalyzes the conversion of pyruvate (PA) to lactic acid (LA), and elevated levels of lactic acid can lead to extracellular acidosis, which in turn promotes tumor cell invasion, angiogenesis, and metastasis (69).

Glabridin significantly inhibited the expression of glycolysis-related genes HK-2 and LDHA in melanoma cells, and reduced levels of lactate (LD) and ATP in the cell culture medium. Furthermore, animal studies demonstrated that glabridin intervention significantly slowed tumor tissue growth in mice, resulting in up-regulation of cellular Bax expression and down-regulation of B-cell lymphoma-2 (Bcl-2), HK-2, and LDHA expression in tumor tissues (37). During glycolysis, glucose transporter protein-1 (GLUT-1) is a key protein responsible for transporting glucose into the cell and maintaining the intracellular glucose concentration (70). Li et al. (71) found that glabridin significantly downregulated GLUT-1 expression and inhibited the glycolytic pathway in MDA-MB-231 breast cancer cells, regulating their energy metabolism. Therefore, the mechanism of apoptosis induced by glabridin may be related to its regulation of the expression of glycolysis-related genes.

Inhibition of the glycolytic pathway as a novel cancer therapeutic strategy has shown initial success in tumor models such as melanoma and breast cancer. Glabridin exhibits anti-tumor potential by modulating the glycolytic pathway and has demonstrated remarkable effects in several cell lines and animal models. However, the inhibition of glycolysis may be accompanied by metabolic adaptation and the development of drug resistance. Therefore, precisely regulating the glycolytic pathway to enhance therapeutic effects and prevent the development of drug resistance remains a key focus for future research.

Mitochondria play a crucial role in regulating energy metabolism and apoptosis. In cancer cells, mitochondria overproduce reactive oxygen species (ROS), which contribute to cancer progression by inducing genomic instability, modifying gene expression, and participating in signaling pathways (72).

Yang et al. found that glabridin significantly inhibits the proliferation of bladder urothelial carcinoma cells and induces apoptosis (38). In a nude mouse model, glabridin significantly inhibits tumor growth and prolongs the survival time of tumor-bearing mice. The mechanism may involve glabridin-induced permeabilization of the outer mitochondrial membrane, which leads to the release of mitochondrial cytochrome c (CYCS) and subsequently triggers apoptosis. In addition, glabridin promotes vacuole formation in the cytoplasm of MDA-MB-231 breast cancer cells, causing loss of mitochondrial membrane potential and ROS production, leading to mitochondrial dysfunction and cancer cell apoptosis (73).

The role of glabridin in bladder and breast cancer cells reveals its potential to induce apoptosis through ROS production and loss of mitochondrial membrane potential. This mechanism may have broad applications in cancer therapy, as inducing cancer cell death through targeting the mitochondrial pathway is a promising strategy to overcome drug resistance. However, precisely regulating this process to avoid damage to normal cells remains a key focus for future research.

EGFR is a receptor tyrosine kinase commonly associated with cancer progression and poor prognosis. Inhibition of EGFR tyrosine kinase activity is considered a promising strategy for cancer treatment (74). Studies have shown that EGFR signaling is closely linked to breast cancer development and resistance to cytotoxic drugs (75).

Through molecular docking, ADMET profiling, and pharmacophore modeling, it was found that glabridin is an effective EGFR inhibitor, with an optimal binding affinity of -7.63 kcal/mol, comparable to the highly effective anti-cancer drug afatinib, and has demonstrated good efficacy in the treatment of breast cancer (76). Zhu et al. (77) found that glabridin can reduce the viability of breast cancer SK-BR-3 cells and induce apoptosis. Further studies showed that glabridin down-regulated the levels of phosphorylated epidermal growth factor receptor (P-EGFR) and phosphorylated protein kinase B (P-AKT) and promoted the expression of cysteine-aspartic acid protease 3 (caspase-3), cysteine-aspartic acid protease 8 (caspase-8), and cysteine-aspartic acid protease 9 (caspase-9), indicating that glabridin exerts its anti-cancer effects by regulating the activation of the EGFR signaling cascade. For detailed information, please refer to Table 2.

The phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is a critical signaling pathway in various cancers, exerting extensive regulatory effects on cell survival, growth, migration, metabolism, and angiogenesis (79).

Tan et al. (80) found that glabridin significantly inhibits the proliferation of prostate cancer cells. Network pharmacology and molecular docking results showed that the PI3K/Akt pathway is key to this process. In vitro experiments showed that glabridin significantly inhibits Akt phosphorylation, suggesting it inhibits prostate cancer cell proliferation by regulating the PI3K/Akt pathway. Zhang et al. (81) also confirmed this view in their study, finding that glabridin promoted ROS signaling in prostate cancer cells in a dose-dependent manner. The excessive production of ROS is an important marker of cancer and can regulate a variety of tumor-related signaling pathways (82). Glabridin can promote apoptosis by inhibiting PI3K/Akt signaling via ROS, enhancing caspase-3 activity, and increasing the Bcl-2-associated X protein (Bax)/Bcl-2 expression ratio.

The mammalian target of rapamycin (mTOR) is a protein kinase that regulates cell proliferation, survival, metabolism, and immunity. It plays an important role in many human cancers and can promote tumor cell growth and metastasis through multiple mechanisms (83). Li et al. (84) investigated the effect and molecular mechanism of glabridin on inhibiting the proliferation of colon cancer cells. After glabridin intervention, the expression of PI3K, Akt, and mTOR proteins, as well as downstream molecules MMP-9, MMP-2, and Bcl-2, was significantly reduced, while the expression of Bax, caspase-3, and caspase-9 proteins was significantly increased. The mechanism of action may be related to the inhibition of the PI3K-Akt-mTOR signaling pathway.

JNK is a member of the mitogen-activated protein kinase (MAPK) family (85) and plays a role in regulating signaling pathways involved in tumor cell proliferation, migration, and apoptosis. It is regarded as a potential target for cancer therapy (86). p38 MAPK is also a member of the MAPK family and can be activated by inflammatory factors and various environmental stresses. These kinases are key components of signal transduction cascades used by cancer cells to sense and adapt to their environment (87).

Studies have found that glabridin regulates JNK1/2 and P38 MAPK phosphorylation, downregulates the anti-apoptotic protein Bcl-2 and procaspase-9, and upregulates Bax and caspase-3, inhibiting colorectal cancer cell proliferation (88). Huang et al. investigated the molecular mechanism of glabridin’s anti-cancer effects in human promyelocytic leukemia and found (89) that glabridin upregulates the phosphorylation of P38 MAPK and JNK1/2 in a time- and dose-dependent manner, promoting the activation of caspase-3, caspase-8, and caspase-9, thereby inhibiting the proliferation of acute myeloid leukemia (AML) cell lines (HL-60, MV4-11, U937, and THP-1). For detailed information, please refer to Table 3.

Ultraviolet B (UVB) is considered a major environmental factor detrimental to human health. It can activate various signal transduction pathways and induce the expression of multiple specific genes, which are the main mechanisms behind skin aging and cancer development (118). Therefore, it is important to prevent and reverse UVB damage to reduce the incidence of skin cancer. A study on the anti-photoaging properties of glabridin found that glabridin effectively attenuated the levels of pro-inflammatory factors, including IL-1β, tumor necrosis factor-α (TNF-α), IL-22, and IFN-γ, thereby preventing UVB-induced photoaging in mice and reducing skin inflammation (119). Another study found that glabridin possesses antioxidant activity, can prevent DNA oxidative damage caused by UVB irradiation, and reduces the production of ROS and the activation of apoptosis pathway proteins (120), thereby preventing skin cancer.

It has been reported that the affinity of glabridin for the human estrogen receptor is comparable to that of genistein, the best-known phytoestrogen (22). Abnormally high estrogen levels are associated with an increased incidence of certain cancers, especially breast and endometrial cancer. The International Agency for Research on Cancer (IARC) has classified estrogen and combined estrogen-progestin postmenopausal therapy as known human carcinogens (23). Glabridin exhibits an estrogenic effect in the endometrial cell line Ishikawa, increasing in a dose-dependent manner and potentially reducing the risk of endometrial cancer (121). Another study found that glabridin, in combination with tamoxifen, exhibited estrogenic activity and inhibited cell proliferation (122). Compared to tamoxifen alone, glabridin in combination with tamoxifen reduced the proliferation of MCF-7 cells twofold. This suggests that combining glabridin with tamoxifen may serve as an estrogen replacement therapy to reduce the risk of tamoxifen-associated endometrial cancer.

Liposomes are vesicular structures formed by encapsulating drugs within a lipid bilayer (124). They can significantly enhance the permeability and solubility of drugs and possess high biocompatibility, non-immunogenicity, low toxicity, and biodegradability (125, 126). Thus, they serve as an excellent drug delivery system.

Huang et al. prepared glabridin liposomes using the complex coacervation method and investigated their particle size distribution, in vitro drug release characteristics, and stability. The results showed that glabridin liposomes had superior in vitro drug release compared to pure glabridin in the first 120 minutes. After three months, the mass fraction of glabridin in the liposomes remained at 38.5%, with a retention rate of 96.25% (127). Zhang et al. prepared glabridin liposomes using the thin film dispersion method and evaluated their effects on skin aging. The results demonstrated that glabridin liposomes exhibited lower cytotoxicity compared to pure glabridin and were more effective in inhibiting melanin production (128). Another study employed the ultrasonic emulsification method to prepare glabridin nanoliposomes. The results indicated that glabridin nanoliposomes exhibited excellent sustained release, transdermal absorption, and photostability, thereby enhancing the utilization of glabridin (129).

Wang et al. utilized Confocal Raman Spectroscopy (CRS) to assess the epidermal permeability of glabridin liposomes compared to pure glabridin. The study showed that glabridin liposomes had 3.8 times greater skin permeability than pure glabridin, and liposome encapsulation significantly enhanced its transdermal absorption and bioavailability (130).

Currently, liposomes are regarded as one of the most advanced drug delivery vehicles. Given their excellent biocompatibility and low toxicity, they have been successfully utilized in various small-molecule drugs and large-molecule biologics (131). For glabridin, liposomes significantly enhance its skin penetration and antioxidant activity. However, the significant efficacy of glabridin liposomes in skin cancer requires further experimental verification. Additionally, the production processes of liposomes (e.g., thin-film dispersion and ultrasonic emulsification) have matured (132) and received multiple approvals from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (133), particularly for cancer treatment drugs (134). Therefore, glabridin liposomes are regarded as one of the most promising delivery systems for rapid advancement to clinical applications. However, their high material cost and the necessity of refrigeration post-preparation, owing to the susceptibility of phospholipids to oxidation, limit their long-term stability (135).

Nanosuspension is the dispersions of drug nanoparticles within a liquid medium, typically water, and consists mainly of nanoparticles with sizes ranging from 100 to 1000 nm. To maintain stability, nanosuspensions are generally stabilized with a small amount of surfactant (136, 137).

Wang et al. prepared a glabridin nanosuspension using the anti-solvent precipitation-homogenization method and optimized particle size by evaluating formulation parameters with the Box-Behnken design (138). The optimal formulation consisted of 0.25% glabridin, 0.47% poloxamer 188, and 0.11% polyvinylpyrrolidone K30. The average particle size of the resulting nanosuspension was 149.2 nm with a polydispersity index of 0.254. The results showed that the nanosuspension significantly enhanced the transdermal penetration flux of glabridin both in vitro and in vivo, without any lag phase. After 3 months of storage at room temperature, no significant particle aggregation was observed, and the drug loss was minimal at 5.46%.

Due to the large specific surface area of nanoparticles, nanosuspensions can enhance the stability of drugs in solvents and extend their shelf life (139, 140); they are suitable for topical administration (e.g., eyes, lungs, and skin) (141). Nanosuspensions are relatively inexpensive to produce and simple to scale up. Several nanosuspension formulations have been approved worldwide (142). However, particle aggregation and changes in particle size need to be controlled during long-term storage.

Nanoemulsion is a thermodynamically unstable yet kinetically stable colloidal solution, formed by dispersing droplets with a particle size of less than 100 nm in a different liquid medium. Its composition typically includes water, oil, surfactants, and co-surfactants (143). Nanoemulsions are characterized by low surface tension, good physical stability, high solubility, and ease of preparation (144).

Liu et al. prepared nanoemulsions using various oil phases and compared their physicochemical properties, including apparent solubility, droplet size, and zeta potential, as well as in vitro and in vivo skin permeability and stability (145). Their study identified the eutectic mixture of menthol and camphor as the optimal solvent for glabridin. The solubility of glabridin in the prepared nanoemulsion was 76.6 mg/g, and both its in vitro and in vivo skin permeability were significantly enhanced compared to pure glabridin. Additionally, the nanoemulsion exhibited excellent chemical stability.

Nanoemulsions are highly efficient transdermal absorption systems suitable for local drug delivery (146). For glabridin, Nanoemulsion can enhance its skin absorption rate and stability; however, whether they can improve glabridin’s efficacy against skin cancer requires further experimental verification. The production processes of Nanoemulsion are relatively simple and easy to scale up (147). Currently, many approved products in cosmetics and pharmaceuticals utilize Nanoemulsion (141). However, the chemical stability of Nanoemulsion requires improvement, as they may undergo phase separation at extreme temperatures (high or low) (148).

Nanoparticles are solid particles sized between 10 and 1000 nm, created using nanotechnology to dissolve or encapsulate drugs within a polymer carrier material (149). These nanoparticles can target drug delivery to tumors or diseased tissues (150), exhibiting high drug loading, high encapsulation efficiency, and controlled drug release (151).

Li et al. discovered that glabridin-loaded nanoparticles not only possess antioxidant activity but also specifically accumulate in the spleen to inhibit inflammatory responses (12). Chen et al. employed an ionic-gelation method to prepare glabridin nanoparticles by blending glabridin with chitosan (CS) and poly-γ-glutamic acid (γ-PGA). The results indicated that the appearance and particle size of the nanoparticles remained stable after 90 days, with an encapsulation rate of 88.30 ± 0.54% and a drug loading rate of 26.47 ± 0.73% (152).

The preparation processes of nanoparticles are well-established, with methods such as solvent evaporation and ultrasound widely applied in industrial production (153). Currently, various nanoparticle drugs have been approved for cancer treatment (154), and their high targeting and controlled release properties demonstrate significant potential in clinical trials for cancer therapies. However, different types of nanomaterials exhibit significant variability in toxicity and metabolic pathways, which may lead to potential immune responses and cumulative toxicity; therefore, rigorous safety evaluations are still required for clinical applications (155).

Nanocomplexes are nano-aggregates formed by non-covalent interactions between carrier molecules, such as proteins or oligosaccharides, and drugs (156), which can improve the physicochemical properties of drugs, increasing solubility, encapsulation rate, and bioavailability (157).

Chitosan is a natural polysaccharide widely utilized in drug delivery applications owing to its excellent biocompatibility and biodegradability (158). Su et al. studied the stability of glabridin in the chitosan-glabridin nanocomplex, finding that the encapsulation rate of glabridin in the nanocomplex could reach up to 84%, significantly enhancing stability in aqueous solution and under ultraviolet light (159). Beta-lactoglobulin (β-Ig) is an essential milk protein widely utilized in food and drug delivery systems owing to its excellent biocompatibility and biodegradability (160). Based on the fact that β-lg readily solubilizes in water and binds many small hydrophobic molecules, Wei et al. developed a novel nanocomplexed glabridin with β-lg using an antisolvent precipitation method (161). Molecular docking modeling showed that glabridin binds to β-lg through hydrophobic and hydrogen bond interactions, increasing its solubility in aqueous solution by 21 times. At the same concentration, nanocomplexed glabridin with β-lg shows better 2,2-diphenyl-1-pyridinium hydrazone and 2,2’-azino-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging capacities compared to pure glabridin. Therefore, the nanocomplexation of β-lg with glabridin, which enhances the solubility of glabridin in aqueous systems, offers a promising opportunity for β-lg to serve as an effective carrier molecule.

Nanocomplexes enhance drug stability and solubility, effectively preventing rapid metabolism or degradation within the biological environment (162). They perform excellently in localized and targeted drug delivery, demonstrating significant potential for cancer treatment (163). However, the long-term stability of nanocomplexes in vivo and their potential immune response risks require further investigation.

Metal-organic frameworks (MOFs) are porous materials formed by the coordination of metal ions or metal clusters with organic ligands. Compared to other nanomaterials, MOF nanoparticles have several advantages, including adjustable pore size, low density, and high surface area (164, 165). These characteristics have led to the increasing use of MOFs as carriers in drug delivery systems in biomedical research, particularly for the delivery of anticancer drugs (166).

ZIF-8 is a special metal-organic framework formed by the self-assembly of zinc ions (Zn²⁺ >) and 2-methylimidazole (2-MIM). In addition to the advantages of other MOFs, ZIF-8 shows high stability in aqueous solutions due to the strong interaction between Zn²⁺ and 2-MIM. Chen et al. prepared a ZIF-8 metal-organic framework (MOF) encapsulating glabridin using the anti-solvent precipitation method (167). The drug encapsulation efficiency was 98.67%, and pH-controlled release of glabridin was achieved. Additionally, cell experiments demonstrated that the MOF significantly enhanced the antioxidant activity, melanin-inhibiting activity, and bioavailability of glabridin.

MOFs can respond to external stimuli (e.g., temperature, light, pH) by adjusting their pore structures to enable controlled drug release (168), demonstrating significant potential in targeted drug delivery, gene therapy, and related fields. However, the incorporation of metal components raises concerns about the potential biotoxicity and biodegradability of MOFs, which remain insufficiently verified (169), posing challenges for safety assessments in biomedical applications.

An inclusion complex is a special complex formed when a drug is partially or completely encapsulated within the cavity structure of a host molecule (170). Cyclodextrin is a cyclic oligosaccharide synthesized by cyclodextrin glucosyltransferase (CGRase) using starch as a substrate (171). Its hydrophilic outer surface and relatively hydrophobic central cavity can form complexes with drugs, thereby enhancing their solubility and stability (172, 187).

Wei et al. employed a co-evaporation method to prepare a complex of glabridin and hydroxypropyl-β-cyclodextrin (HP-β-CD). The results demonstrated that at 25°C, the solubility of the complex in pure water was 40.74 ± 0.44 mM, which was 1852 times higher than that of glabridin. In vitro experiments revealed that the DPPH free radical scavenging capacity and the tyrosinase inhibitory activity of the complex were enhanced by approximately 9 and 20 times, respectively (173).

Li et al. demonstrated that the encapsulation efficiency and drug loading capacity of the glabridin/HP-β-CD inclusion complex were 90.03% and 14.51%, respectively. The saturation solubility of the inclusion complex was 109.36 mg/mL. The cumulative dissolution rates in gastric and intestinal juices after 1 hour were 15.75 and 12.4 times higher than those of glabridin, respectively, while the cumulative release rate over 24 hours was 53 times that of glabridin. The uptake of Caco-2 cells was 0.349 mg/g, significantly higher than that of glabridin (0.039 mg/g). These results indicate that the glabridin/HP-β-CD inclusion complex significantly enhances the dissolution and release of glabridin, thereby increasing its bioavailability (174). Thus, the glabridin/HP-β-CD inclusion complex is expected to be an ideal form of glabridin for drug delivery.

Wang et al. developed a novel inclusion complex, sulfobutylether-β-cyclodextrin/glabridin, using the freeze-drying method. The solubility of this inclusion complex was 1889 times higher than that of glabridin. Moreover, this inclusion complex exhibited excellent biocompatibility, along with significant antibacterial, anti-inflammatory, and antioxidant activities, and effectively accelerated the healing of skin damage (175).

Yao et al. prepared 2-sulfobutyl-β-cyclodextrin/glabridin inclusion complexes using freeze-drying, spray-drying, and kneading methods. The saturation solubility of these complexes was greater than 83 mg/mL. The encapsulation efficiency and drug loading capacity of the inclusion complex prepared by freeze-drying were 86.09% and 22.39%, respectively. The cumulative dissolution rates in gastric and intestinal fluids, as well as the antiproliferative activity against the human liver cancer cell line (HepG-2), were significantly higher than those of glabridin (176).

Cyclodextrin inclusion complex significantly enhances the solubility of glabridin and effectively improves the bioavailability of drugs, making them suitable for oral and topical administration (177). However, the production costs of cyclodextrin complexes remain relatively high (178). Studies indicate that cyclodextrin complexes are valuable not only for cancer and inflammation treatment but also for delivering novel small molecule and peptide drugs (133). Nonetheless, further toxicological and biocompatibility studies are required to ensure their safety across various administration routes (179, 180).

Polymeric micelles are thermodynamically stable colloidal solutions that form through the self-assembly of synthetic amphiphilic block copolymers in aqueous environments. Their hydrophilic shell and nanoscale particle size facilitate drug release within the body and enhance drug concentration at the target site (181).

Partially myristoylated chitosan pyrrolidone carboxylate (PMCP) is a cationic, amphiphilic derivative of chitosan. Senio et al. employed PMCP emulsification to develop novel, nanoparticle-sized cationic polymeric micelles encapsulating glabridin (182). The skin permeability and melanin inhibition efficacy of the polymeric micelles were evaluated using a human skin model. The results showed that the glabridin dose absorbed 24 hours after applying polymeric micelles was approximately four times higher than that of conventional oil-in-water micelles with Tween 60 (control), significantly inhibiting melanin production. These polymeric micelles hold significant promise as a transdermal drug delivery system for treating skin pigmentation.

Polymer micelles represent a novel delivery system that has emerged in recent years. For glabridin, polymer micelles enhance drug transdermal absorption and stability, making them suitable for intravenous injection and targeted drug delivery (183, 184). However, the preparation process is complex, with stringent requirements for storage and transportation conditions. Large-scale production requires further optimization (185). Currently, the regulatory pathway for polymer micelles remains unclear, and their large-scale clinical application continues to face challenges (186).

In summary, new drug delivery systems for glabridin, including liposomes, cyclodextrin complexes, polymer micelles, nanoparticles, nanoemulsions, nanosuspensions, and nanocomposites, have been extensively researched. These systems have made significant strides in improving the solubility, stability, and bioavailability of glabridin. Notably, glabridin is widely utilized in the cosmetics industry for its whitening effects. Current drug delivery systems for glabridin primarily focus on enhancing skin permeability and anti-melanin effects. However, there is a notable lack of research on its release rate, stability, accumulation, and targeting within the body. Furthermore, existing studies have mainly addressed issues related to drug distribution and release, with insufficient consideration of disease pathology and innovative treatment strategies. Future research should prioritize understanding disease pathogenesis and utilize functionalized materials sensitive to pH, redox conditions, temperature, light, sound, and magnetism. This approach aims to create synergistic effects between drugs and carriers, as well as between different drugs, while integrating diverse treatment methods to further explore the potential of glabridin in disease treatment. For detailed information, please refer to Table 5.