Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting
Abstract
:1. Introduction
2. Major Factors Limiting Brain Targeting
2.1. Blood–Brain Barrier
2.2. Blood–Cerebrospinal Fluid Barrier
2.3. Blood–Brain Tumor Barrier
3. The Application of Natural Products in the Treatment of the CNS
3.1. Alzheimer’s Disease
3.2. Parkinson’s Disease
3.3. Stroke
3.4. Glioma
4. Application of the Trojan Horse Strategy in Drug Delivery to the Central Nervous System
4.1. Receptor-Mediated Transcytosis
4.1.1. Transferrin Receptor
4.1.2. Interleukin-13 Receptor
4.1.3. Lactoferrin Receptor
4.1.4. Low-Density Lipoprotein Receptor
4.1.5. Low-Density Lipoprotein Receptor-Related Protein
4.1.6. Integrin
4.1.7. Nicotinic Acetylcholine Receptor
4.1.8. Nucleolin
4.2. Carrier-Mediated Transport
4.2.1. Glucose Transporters
4.2.2. L-Type Amino Transporters 1
4.3. Adsorptive-Mediated Transcytosis
4.4. Other Emerging Delivery Pathways
4.4.1. Cell-Penetrating Peptides
4.4.2. Cell-Mediated Drug Delivery
Mesenchymal Stem Cells
Macrophage
Red Blood Cells
Neutrophils
5. Limitations of Trojan Horse Delivery Strategies
- The Biocompatibility of Nanocarriers: The safety of nanomaterials in the body is crucial. Some nanomaterials may trigger toxic or immune responses and could even cause long-term side effects to the human body. Therefore, it is necessary to develop safer and more efficient nanocarriers to ensure their widespread application does not adversely affect patient health.
- The Precise Control of Drug Release: The rate and timing of the drug release are crucial in disease treatment. Adjusting the drug release process according to the needs of different disease stages and targeted sites has become a current research hotspot. This requires an in-depth understanding of the molecular changes in the disease process and precise control of the carrier’s release behavior.
- Insufficient Targeting Specificity: Although nanocarriers theoretically have some targeting ability, in practical application, drug delivery may still exhibit “off-target” phenomena. This means drugs may not only concentrate in the lesion area but could also affect healthy tissues, leading to side effects. Enhancing the targeting capability of carriers and ensuring drugs act only at target sites remains a significant research topic.
- Immune Response and Long-term Toxicity: Some nanocarriers, upon entering the body, may trigger immune responses, especially during long-term treatment, where cumulative effects could lead to potential long-term toxicity. Thus, reducing immune rejection and long-term toxicity remains one of the bottlenecks in current technological development.
6. Conclusions and Prospects
Author Contributions
Funding
Conflicts of Interest
References
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Natural Medicine Monomers | Ligands | Receptors | Nano-Drug Delivery System | Application | Ref. |
---|---|---|---|---|---|
PTX | Tf | TfR | TF/TAT-PTX/DOX-LP | Glioma | [160] |
Vincristine/Tetrandrine | Tf | TfR | Tf modified vincristine plus tetrandrine liposomes | Glioma | [161] |
Resveratrol | Tf | TfR | f-PEG-PLA-RES nanoparticles | GBM | [162] |
Muscone | RI7217 | TfR | Muscone and RI7217 co-modified DTX liposomes | Glioma | [163] |
Elemene (ELE) | Tf | TfR | Tf-ELE/CTX@BLIP | Glioma | [164] |
Vincristine (VCR) | T12, B6, and T7 | TfR | T12/B6/T7-LS/VCR | Glioma | [165] |
Borneol | Pep-1 | IL-13R | DSPE-PEG-Bor | Glioma | [166] |
PTX | Pep-1 | Interleukin-13 receptor α2 (IL-13Rα2) | Pep-NP-PTX | Glioma | [167] |
PTX | Pep-1 | Interleukin-13 receptor α2 (IL-13Rα2) | PTX loaded Pep-1 and CGKRK peptide-modified PEG-PLGA nanoparticle (PC-NP-PTX) | Glioma | [168] |
Quercetin (QU) | Lf | LfR | RMP-7-Lf-QU-LS | AD | [169] |
Borneol | Lf | LfR | Borneol and lactoferrin co-modified nanoparticles (Lf-BNPs) | PD | [170] |
Huperzine A | Lf | LfR | HupA Lf-TMC NPs | AD | [171] |
Muscone | Lf | LfR | Lf-LP-Mu-DTX | Glioma | [172] |
Rosmarinic acid | Cross-reacting material 197 (CRM197)/ApoE | Diphtheria toxin receptor/LDL-R | CRM197-ApoE-RA-PAAM-CH-PLGA | AD | [173] |
Berberine | The attachment of plasma apolipoprotein (ApoE and ApoB) to Tween 80 | LDL-R | PTX-Tween 80-BBR + FA-Lip | Glioma | [174] |
PTX | Peptide-22 | LDL-R | PNP–PTX | Glioma | [175] |
PTX | Angiopep-2/A15 | LRP/CD133 | DP-CLPs-PTX-siRNA nanocomplex | Glioma | [176] |
Isoliquiritigenin (ISL) | Angiopep-2 | LRP-1 | ISL loaded micelle prepared with DSPE-PEG2000 as the drug carrier modified with angiopep-2 | Ischemic stroke | [177] |
Salidroside/Icariin | Angiopep-2 | LRP-1 | Ang-Sal/Ica-Lip | AD | [178] |
PTX | R8-RGD | Integrin receptors expressed on C6 cells | PTX-R8-RGD-lipo | Glioma | [179] |
PTX | R8-c(RGD) (R8c(RGD)-Lip) | Integrin αvβ3 | PTX-R8-c(RGD)-Lip | Vasculogenic mimicry and cancer ctem cells in malignant glioma | [180] |
Vincristine/Tetrandrine | RGD | Integrin αvβ3 | RGD-modified vinorel- bine plus tetrandrine liposomes | Glioma | [181] |
PTX/Naringenin | Cyclic RGD peptide sequence (Arg-Gly-Asp) | Integrin αvβ3 | RGD-modified PTX-NAR loaded SLNs | GBM | [182] |
PTX | iRGD | Integrin αvβ3 | Co-administration of MT1-AF7p-conjugated PEG-PLA with iRGD | GBM | [183] |
PTX | TR peptide | Integrin αvβ3 | PTX-TR-Lip | Glioma | [184] |
PTX | RVG | nAChR | PTX-cholesterol complex (PTX-CHO) | Glioma | [185] |
Baicalin | RVG29 peptide | nAChR | RVG29 peptide-modified BA-PEG-PLGA RNPs | Neuroprotection in cerebral ischemia | [186] |
PTX | RVG | nAChR | RVG-PTX-NPs | Glioma | [187] |
Shikonin | HA/AS1411 | CD44/Nucleolin | AS1411 aptamer/hyaluronic acid-bifunctionalized microemulsion co-loading shikonin and docetaxel | Glioma | [188] |
Shikonin | AS1411/T7 (HAIYPRH) | Nucleolin/Tfr | Fe3O4@T7/AS1411/DTX&SKN-M | Glioma | [189] |
Natural Medicine Monomers | Substrate | Transporters | Nano-Drug Delivery System | Application | Ref. |
---|---|---|---|---|---|
PTX | Multifunctional ginsenoside Rg3-based liposomal system (Rg3-LPs) | GLUT1 | Rg3-PTX-LPs | Glioma | [243] |
PTX | Glucose-RGD (Glu-RGD) | GLUT1 and integrin αv β3 | PTX-Glu-RGD-Lip | Glioma | [244] |
PTX | Glucose-vitamin C (Glu-Vc) derivative | GLUT1/SVCT2 | Glu-Vc-PTX-Lip | Glioma? | [245] |
PTX/Artemether | MAN | GLUT1 | PTX-Artemether-MAN-TPGS1000-Lip | Glioma | [246] |
Curcumin | Glycopeptide (g7) | GLUT1 | g7-PLGA-NPs-Cur | AD | [247] |
PTX | Glycosylated A7R derivative | GLUT1 | 9G-A7R-PTX | Glioma | [248] |
Curcumin | MAN | GLUT1 | Curcumin and quinacrine liposomes modified with MAN | Glioma | [249] |
Resveratrol | MAN | GLUT1 | Epirubicin plus resveratrol liposomes modified with MAN (MAN-EPI-RES-L | Glioma | [250] |
Rrsolic acids (UA)/epigallocatechin 3-gallate (EGCG) | MAN | GLUT1 | MAN-Ursolic acids plus EGCG liposomes | Glioma | [251] |
Quercetin | Glucose | GLUT1 | Glucose-modified QU liposome (QU-Glu-Lip) | Neurodegenerative diseases (NDDs) | [252] |
Artemisinin | Cholesterol-undecanoic acid-glucose conjugate | GLUT1 | na-ATS/TMP@lipoBX | Cerebral malaria (CM) | [253] |
Ferulic acid (FA) | L-phenylalanine | LAT1 | L-phenylalanine-amino/ester-Ferulic acid | AD | [254] |
Vinblastine | Derivatives of probenecid (PRB) | LAT1 | PRB-vinblastine | Improves efflux transporter-related MDR of brain-targeted anti-cancer agents | [255] |
Natural Medicine Monomers | Electropositive Components | Nano-Drug Delivery System | Application | Ref. |
---|---|---|---|---|
Vincristine/ tetrandrine | Polyethylenimine (PEI)/ Vapreotide (VAP) | Vinorelbine plus tetrandrine liposomes modified with PEI and VAP | Glioma stem cells (GSCs) | [276] |
Vinorelbine | DC-Chol | WGA (wheat germ agglutinin)-modified vinorelbine cationic liposomes | Glioma | [277] |
Natural Medicine Monomers | Ligands | Nano-Drug Delivery System | Application | Ref. |
---|---|---|---|---|
PTX | R8-RGD | PTX-R8-RGD-lipo | Glioma | [179] |
PTX | R8-c(RGD) (R8c(RGD)-Lip) | PTX-R8-c(RGD)-Lip | Vasculogenic mimicry and cancer ctem cells in malignant glioma | [180] |
PTX | MSCs | Ptx-encapsulated PLGA nanoparticles (NPs) | Glioma | [278] |
Baicalin | Macrophage membrane | Macrophage membrane-modified BA-LP (MM-BA-LP) | Cerebral ischemia reperfusion injury | [279] |
PTX | Neutrophils (NEs) | PTX-NEs | Penetrates the brain and suppress the recurrence of glioma | [280] |
Resveratrol | Red blood cell | RVG/TPP NPs@RBCm | AD | [281] |
Curcumin | MSCs | cRGD-Exo-cur | IS | [282] |
Curcumin | Macrophage RAW264.7 cells | Ex-cur | Alleviates cerebral ischemia-reperfusion injury | [283] |
Leonurine | Neutrophil membrane | Leo@NM-Lipo | IS | [284] |
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Lei, K.; Zhou, L.; Dan, M.; Yang, F.; Jian, T.; Xin, J.; Yu, Z.; Wang, Y. Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting. Pharmaceutics 2025, 17, 280. https://doi.org/10.3390/pharmaceutics17030280
Lei K, Zhou L, Dan M, Yang F, Jian T, Xin J, Yu Z, Wang Y. Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting. Pharmaceutics. 2025; 17(3):280. https://doi.org/10.3390/pharmaceutics17030280
Chicago/Turabian StyleLei, Kelu, Lanyu Zhou, Min Dan, Fei Yang, Tiantian Jian, Juan Xin, Zhigang Yu, and Yue Wang. 2025. "Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting" Pharmaceutics 17, no. 3: 280. https://doi.org/10.3390/pharmaceutics17030280
APA StyleLei, K., Zhou, L., Dan, M., Yang, F., Jian, T., Xin, J., Yu, Z., & Wang, Y. (2025). Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting. Pharmaceutics, 17(3), 280. https://doi.org/10.3390/pharmaceutics17030280