Currently, in the research of nano-drug delivery systems, there exist issues such as poor biocompatibility, short blood circulation lifetime, insufficient active targeting, and low permeability through biological membranes. Specifically, in the blood circulation, a large amount of non-specific proteins and biomolecules tend to adsorb onto the surface of nanoparticles, forming a protein interference layer, which greatly hinders the nano-carriers from reaching the target site as designed and exerting their intended therapeutic effects. Therefore, new drug delivery systems based on the biomimicry of various cells in the body's circulatory system have emerged, gradually becoming a research hotspot in the field of life sciences in recent years. Among them, platelet and platelet membrane biomimetic drug delivery systems have attracted significant attention from researchers. As an inherent component of the organism, platelets can evade immune system clearance and are closely related to physiological processes such as endothelial injury repair, immune response, atherosclerosis formation, neurodegeneration, and tumor growth and metastasis. During their participation in these bodily reactions, platelets can effectively target and accumulate at the reaction sites. Therefore, platelet membrane biomimetic drug delivery systems show great application prospects in tumor targeting, vascular endothelial injury repair, and coagulation.

Based on drug loading methods and assembly techniques, platelet and platelet membrane biomimetic drug delivery systems can be classified into three categories: carriers where drugs are covalently conjugated to platelet membranes, carriers where drugs are directly encapsulated within platelets, and nano-carriers coated with platelet membranes.

（1）Carriers where drugs are covalently conjugated to platelet membranes utilize natural platelets as a medium, coupling or expressing drugs onto platelet membranes through chemical covalent bonds or bioengineering techniques. These carriers leverage the platelet's targeted binding capabilities at tumor tissues, circulating tumor cells (CTC), damaged blood vessels, and other sites to deliver drugs to the disease sites. Following platelet activation, drug-containing microparticles are released to exert therapeutic effects.

（2）Carriers where drugs are directly encapsulated within platelets involve encapsulating drugs within natural platelets using methods such as chemical methods, electroporation, endocytosis, hypotonicity, and lipid fusion. Utilizing the protection of natural platelets can enhance drug stability, reduce adverse reactions, and improve therapeutic effects.

（3）Platelet membrane-coated nano-carriers are functional delivery systems that utilize electrostatic adsorption to coat the surface of nano-carriers with platelet membranes. These membranes can further be modified to enhance their functionality. Platelets extracted from fresh blood, after processes such as separation, purification, freeze-thawing or lysis, and centrifugation, can still retain platelet membrane proteins well and exert their original physiological characteristics after being coated onto the surface of nano-carriers. This type of drug delivery system provides nano-carriers with a biological camouflage coat, which not only improves biocompatibility and immune evasion capabilities but also allows for chemical modification using free amino or carboxyl groups on the platelet membrane, thus endowing the carrier system with richer functions.

Applications of Platelet Membrane Biomimetic Carriers

1.Application of Platelet Membrane Biomimetic Nano-carriers in Tumor Targeted Therapy

Platelet membranes express various protein molecules (such as selectins, integrins, etc.) that can bind to tumor cell surface receptors. Therefore, platelet membrane biomimetic carriers possess tumor targeting capabilities and can be used for tumor targeted therapy.

First, platelet membrane biomimetic nano-carriers can enhance the efficacy of conventional chemotherapeutic drugs. For example, platelet membrane-coated silica particles have been used to target TRAIL delivery to tumor blood vessels to kill tumor cells. By retaining the intact composition of membrane proteins and glycans on the platelet membrane that are related to tumor cell targeting, as well as the CD47 protein that participates in host cell self-recognition, in an immunodeficient mouse model treated with breast cancer cells, TRAIL-loaded silica particles coated with platelet membranes not only targeted tumor tissue but also reduced phagocytosis by phagocytic cells. When TRAIL-loaded silica particles coated with platelet membranes were implanted into lung vascular microthrombi associated with tumor cells, a significant reduction in lung metastasis was observed. In the treatment of myeloma using bortezomib nano-carriers coated with platelet membranes, tissue-type plasminogen activator was modified onto the platelet membrane through biotin-streptavidin affinity, and alendronate was used as a targeting ligand to modify the platelet membrane for chelating calcium ions in the bone microenvironment, enhancing drug accumulation in bone tissue and reducing off-target effects. This nano-carrier has both thrombolytic and targeted localization of myeloma functions, enhancing the drug utilization rate of bortezomib, reducing adverse reactions and thrombotic complications, and ultimately enhancing the therapeutic effect of multiple myeloma.

Secondly, platelet membrane biomimetic nano-carriers can enhance the efficacy of photodynamic therapy and photothermal therapy. Nanocarriers coated with platelet membranes are used to co-deliver tungsten oxide and metformin. Among them, metformin can improve the therapeutic effect of tungsten oxide photodynamic therapy by reducing oxygen consumption. The platelet membrane not only protects tungsten oxide from oxidation but also賦予賦予 it the ability to evade the immune system. Additionally, through passive enhanced permeability and retention (EPR) effect and the active adhesion of platelet membranes to cancer cells, the nanoparticles are promoted to accumulate at the tumor site, inducing tumor cell apoptosis, inhibiting tumor growth, and enhancing the therapeutic effects of tungsten oxide-mediated photodynamic therapy and photothermal therapy.

Furthermore, platelet membrane biomimetic nano-carriers can also play a role in enhancing radiosensitization and anti-tumor immune responses. By coating platelet membranes onto the surface of bismuth sulfide-loaded mesoporous silica nanorods, they can achieve tumor targeting, immune evasion, and radiosensitization, thus enabling personalized radio-photothermal therapy. By encapsulating sulfasalazine into magnetic nanoparticles Fe3O4 and camouflaging them with platelet membranes, drug-loaded biomimetic nano-carriers can inhibit the uptake of cysteine in tumor cells, effectively trigger tumor cell ferritin deposition, and induce tumor-specific immune responses. This approach can significantly enhance the efficacy of PD-1 blockers in mouse models of metastatic breast cancer. Platelet membrane biomimetic nano-carriers can also achieve integrated imaging-guided diagnosis and treatment. By coating platelet membranes onto Fe3O4 magnetic nanoparticles, these nanoparticles possess both platelet immune evasion and cancer targeting abilities, as well as Fe3O4 magnetic and optical absorption properties. They can enhance tumor magnetic resonance imaging while enabling photothermal therapy.

Compared to cell membrane biomimetic nano-carriers derived from other cell types, platelet membrane biomimetic nano-carriers have more extensive applications and significant advantages in tumor-targeted therapy. The specific proteins expressed on their membranes can not only specifically target tumors expressing specific receptors but also specifically adhere to tumor neovascular regions, exhibiting efficient active targeted therapeutic and immune evasion capabilities. At the same time, they can reduce the adverse reactions caused by nanoparticle accumulation in healthy tissues and organs, demonstrating high biosafety characteristics.

2.Application of Platelet Membrane Biomimetic Nano-carriers in Cardiovascular and Cerebrovascular Diseases

Extensive research has shown that ischemia in the heart and brain system can cause vascular injury, exposing components such as subendothelial matrix collagen, fibronectin, and vascular pseudohemophilia factor, recruiting platelets, thereby causing platelet accumulation and direct binding to damaged endothelial cells. Therefore, platelet membrane biomimetic carriers have broad application prospects in cardiovascular and cerebrovascular diseases.

In the treatment of cardiovascular and cerebrovascular diseases, current research has focused on targeted therapies for ischemic diseases such as myocardial infarction, myocardial ischemia/reperfusion injury, atherosclerosis, and stroke. For example, when platelet nanovesicles are modified on the surface of cardiac stem cells through membrane fusion, it is found that platelet membrane modification does not affect the viability and function of stem cells in vitro, nor does it cause coagulation reactions or immune cell aggregation. At the same time, it can enhance the binding force between stem cells and collagen surfaces as well as denuded aortas, enhance the targeting of stem cells to myocardial infarction, and promote the accumulation of stem cells in the heart, thereby improving the therapeutic effect. By combining the secretory proteome of cardiac stromal cells with PLGA to prepare nanocells (NC), and then coating NC with platelet membranes carrying prostaglandin E2, it is found that the coated NC can significantly enhance cardiac function, inhibit cardiac remodeling, increase circulating cardiomyocytes, promote the activation of endogenous stem/progenitor cells, and angiogenesis. Using platelet membranes to encapsulate PLGA nanoparticles for targeted delivery of rapamycin to treat atherosclerotic plaques in ApoE-/- mice, the results showed that the nanoparticles can specifically accumulate in atherosclerotic plaques, significantly reduce atherosclerotic areas by inducing macrophage autophagy, and enhance the stability of atherosclerotic plaques. The targeted nanoparticles not only enhance the anti-atherosclerotic drug activity but also reduce adverse reactions such as dyslipidemia caused by free rapamycin.

In addition, platelets play a role in hemostasis and coagulation in the body, participating in the formation of blood clots. Therefore, platelet membrane-coated biomimetic nanoparticles can participate in the regulation of coagulation-related diseases. Using platelet membrane-coated biomimetic nanoparticles to treat immune thrombocytopenic purpura, the nanoparticles retain all the complement proteins on the platelet surface, allowing them to specifically bind to anti-platelet antibodies, preventing the release of pathological antibodies, protecting normal platelets in the circulation, and thus maintaining normal hemostatic function. These biomimetic nanoparticles have high biosafety and a long retention time in the body, making them potential alternatives to anti-platelet antibodies for disease treatment. Nanomotors prepared using platelet membrane-modified silica and platinum, loaded with urokinase and heparin, can be used for targeted thrombolysis and anticoagulation treatment. Research has shown that drug-loaded nanomotors can target and aggregate at thrombus sites, penetrate into the thrombus interior, and significantly enhance thrombolytic effects. Applying platelet membrane-coated PLGA nanoparticles to deliver lumbrokinase to carotid artery thrombus sites has confirmed that platelet membrane-coated nanoparticles have a high affinity for thrombi, superior thrombolytic effects, and can greatly reduce the risk of bleeding.

Platelet membrane biomimetic nano-carriers can not only be used for treatment, but also for disease diagnosis and the integration of imaging and therapeutics. Combining biomimetic nano-carriers with imaging probes can achieve targeted enhanced imaging. The preparation of platelet membrane-coated MRI nano-contrast agents has revealed, through both in vitro and in vivo experiments, that the membrane-coated nano-contrast agents have a high affinity for atherosclerotic plaques, generating sufficient contrast to distinguish the presence of plaques during real-time imaging. At the same time, they can also target and visualize early intimal injury during the formation of atherosclerosis, thus having potential applications in early disease prevention.

Compared with other biomimetic nanoparticles derived from different cell membranes, the platelet membrane biomimetic nano-carriers have the advantage of not only specifically adhering to damaged blood vessels but also actively targeting inflammatory and damaged regions within the blood vessels. This enhances the efficacy of drugs, reduces adverse reactions caused by free drugs, and minimizes the accumulation of nanoparticles in healthy organs and tissues.

3.Other Applications of Platelet Membrane Biomimetic Carriers

Platelet membrane biomimetic carriers not only hold significant research value in the field of oncology and cardiovascular diseases, but also play a unique therapeutic role in other diseases, such as biodetoxification, bacterial infection treatment, gene silencing, and the treatment of rheumatoid arthritis. Some scholars have synthesized platelet membrane nano-motors for the adsorption and separation of platelet-targeted biological agents. Experiments have found that these nano-motors have a strong affinity for adhering to platelet toxins and pathogens, allowing them to selectively bind to shiga toxin, providing a new approach for biodetoxification and targeted treatment of infectious diseases. In a mouse model of methicillin-resistant Staphylococcus aureus infection, targeted delivery of vancomycin using platelet membrane-coated PLGA nanoparticles showed stronger therapeutic effects compared to the pure drug group and the erythrocyte membrane-coated nanoparticle group. The use of platelet membrane-encapsulated metal-organic framework nanoparticles for the delivery of siRNA to achieve targeted gene silencing in vivo has been applied to treat diseases related to siRNA, such as tumors and thyroxin-mediated amyloidosis. Targeted delivery of FK506 using platelet membrane biomimetic nano-carriers has shown high accumulation in inflammatory synovial tissues and significant control over the progression of rheumatoid arthritis.

References:

[1] Xu Jianpei, Xu Qunwei, Wang Xiaoqi, et al. Research Progress on Biomimetic Drug Delivery Systems Based on Platelets and Their Membranes [J]. Journal of China Pharmaceutical University, 2018, 49(06): 653-659.

[2] Lin Ling, Chen Yihan, Jin Qiaofeng, et al. Research Progress of Platelet Membrane Biomimetic Nano-carriers [J]. Chinese Journal of Ultrasound in Medicine, 2021, 30(5): 5.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.