Research Progress on Platelet Membrane Biomimetic Drug Delivery Systems

Currently, in the research of nanoscale drug delivery systems, there are several problems such as poor biocompatibility, short blood circulation lifespan, insufficient active targeting, and low permeability through biological membranes. Particularly in the bloodstream, a large amount of non-specific proteins and biomolecules adsorb on the surface of nano-carriers forming a protein corona layer, which greatly affects the expected therapeutic efficacy of the nano-carriers reaching the targeted site as designed. Therefore, based on the new biomimetic drug delivery systems of various cells in the body's circulatory system, it has gradually become a research hotspot in the field of life sciences in recent years. Among them, platelets and their membrane biomimetic drug delivery system have attracted great attention from researchers. As an inherent component of the body, platelets can escape the 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. Platelets can target and accumulate well in the reactive sites of these body responses. Therefore, the platelet membrane biomimetic drug delivery system shows great potential for application in tumor targeting, endothelial injury repair, and coagulation, etc.

According to the drug loading method and assembly method, platelets and their membrane biomimetic drug delivery system can be divided into three categories: carrier with drugs covalently linked to the platelet membrane, carrier with drugs directly loaded into platelets, and nano-carrier coated with platelet membrane.

The carrier with drugs covalently linked to the platelet membrane is a delivery carrier that uses natural platelets as a medium to chemically covalently link or express drugs on the platelet membrane through biological engineering means. It utilizes the platelet's targeting binding ability in tumor tissues, circulating tumor cells (CTCs), damaged blood vessels and other sites to deliver drugs to the lesion. Then the platelets are activated and release drug-containing microparticles to exert a therapeutic effect.

The carrier with drugs directly loaded into platelets is a delivery carrier that uses various means such as chemical methods, electroporation, phagocytosis, low-permeation, and lipid fusion to load drugs into natural platelets. The protection of natural platelets can improve drug stability, reduce adverse reactions, and enhance therapeutic effects.

The nano-carrier coated with platelet membrane is a functional delivery carrier that coats the platelet membrane on the surface of the nano-carrier through electrostatic adsorption and can further modify its membrane surface. Platelets extracted from fresh blood can still retain platelet membrane proteins well after processes such as separation, purification, freeze-thaw or lytic expansion, centrifugation, etc., and exhibit their original physiological characteristics after being coated on the surface of the nano-carrier. This type of drug delivery system provides a layer of biological camouflage outerwear for the nano-carrier, while improving biocompatibility and immune escape ability, it can also use the free amino or carboxyl groups on the platelet membrane for chemical modification and endow the carrier system with more diverse functions.

The Application of Platelet Membrane Biomimetic Carriers

1. Application of Platelet Membrane Biomimetic Nanocarriers in Targeted Cancer Therapy

Platelet membrane expresses various proteins (such as selectins and integrins) that can bind to receptors on tumor cells. Therefore, platelet membrane biomimetic carriers have tumor targeting properties and can be used for targeted cancer therapy. Firstly, platelet membrane biomimetic nanocarriers enhance the efficacy of conventional chemotherapy drugs. For example, platelet membrane-coated silica nanoparticles can deliver TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand) to tumor blood vessels to kill tumor cells. By retaining the complete composition of membrane proteins and polysaccharides related to tumor cell targeting on platelet membranes, as well as the CD47 protein involved in host cell recognition, platelet membrane-coated silica nanoparticles carrying TRAIL can not only target tumor tissues but also reduce phagocytic clearance by immune cells. Implanting platelet membrane-coated TRAIL-loaded silica nanoparticles into tumor cell-associated pulmonary microthrombi can significantly reduce lung metastasis. In the treatment of multiple myeloma, boronic acid-based proteasome inhibitors are coated with platelet membrane and modified with tissue-type plasminogen activator through biotin-streptavidin affinity, while alendronate is decorated on the platelet membrane as a targeting ligand to chelate calcium ions in the bone microenvironment, thereby enhancing drug accumulation in bone tissue and reducing off-target effects. This nanocarrier, with both thrombolytic and targeted bone marrow localization functions, enhances the drug utilization of boronic acid-based proteasome inhibitors, reduces adverse reactions and the occurrence of thrombotic complications, and ultimately enhances the treatment efficacy of multiple myeloma.

Secondly, platelet membrane biomimetic nanocarriers enhance the efficacy of photodynamic therapy and photothermal therapy. By utilizing platelet membrane-coated nanocarriers co-loaded with tungsten oxide and metformin, metformin can improve the therapeutic effect of tungsten oxide-mediated photodynamic therapy by reducing oxygen consumption. Platelet membranes not only protect tungsten oxide from oxidation but also confer immune escape capabilities. Through passive high permeability and long retention effects and active adhesion to cancer cells mediated by platelet membranes, the accumulation of nanoparticles in tumor sites is promoted, inducing tumor cell apoptosis, inhibiting tumor growth, and enhancing the efficacy of tungsten oxide-mediated photodynamic therapy and photothermal therapy.

In addition, platelet membrane biomimetic nanocarriers can play a role in radiosensitization and enhancing anti-tumor immune responses. By encapsulating platelet membranes in mesoporous silica nanorods loaded with bismuth sulfide, the nanocarriers exhibit tumor targeting, immune escape, and radiation sensitization properties, enabling personalized radio-photothermal therapy. By incorporating pyrrolidinedithiocarbamate within magnetite nanoparticles (Fe3O4) and camouflaging them with platelet membranes, drug-loaded biomimetic nanocarriers can inhibit the uptake of cysteine by tumor cells, effectively induce tumor-specific immune responses, and significantly enhance the efficacy of PD-1 inhibitors in a mouse model of metastatic breast cancer. Platelet membrane biomimetic nanocarriers can also achieve image-guided diagnosis and treatment integration. By wrapping platelet membranes around Fe3O4 magnetic nanoparticles, the nanoparticles possess both platelet immune evasion and cancer targeting abilities, as well as the characteristics of magnetite absorption and light absorption. This enables enhanced tumor magnetic resonance imaging and simultaneous photothermal therapy.

Compared to biomimetic nanocarriers derived from other cell sources, platelet membrane biomimetic nanocarriers have broader applications and significant advantages in targeted cancer therapy. The specific proteins expressed on their membranes not only allow for specific targeting to tumors expressing certain receptors but also enable specific adhesion to the neovascularization area of tumors. This provides efficient active targeting capabilities and immune escape capabilities while reducing adverse reactions from nanoparticle accumulation in healthy tissues and organs, thus possessing high biological safety characteristics.

2. The Application of Platelet Membrane Biomimetic Nanocarriers in Cardiovascular and Cerebrovascular Diseases

Numerous studies have shown that ischemia in the cardiovascular and cerebrovascular systems can cause vascular damage, leading to exposure of components such as subendothelial matrix collagen, fibronectin, and von Willebrand factor. This exposure recruits platelets, resulting in platelet aggregation and direct binding to damaged endothelial cells. Therefore, the application of platelet membrane biomimetic nanocarriers holds great promise in the field of cardiovascular and cerebrovascular diseases.

In the treatment of cardiovascular and cerebrovascular diseases, current research mainly focuses on targeted therapies for ischemic diseases such as myocardial infarction, myocardial ischemia/reperfusion injury, atherosclerosis, and stroke. For example, modifying platelet-derived nanovesicles onto the surface of cardiac stem cells through membrane fusion has been found to enhance the binding strength between stem cells and collagen surfaces and the stripped aorta. This modification does not affect the in vitro activity and function of stem cells, nor does it induce clotting reactions and immune cell aggregation. Moreover, it promotes the aggregation of stem cells in the heart, thereby improving treatment outcomes. By combining the protein composition secreted by cardiac matrix cells with PLGA (poly(lactic-co-glycolic acid)), nano cells (nanocells, NC) can be prepared. These NCs are then coated with platelet membranes carrying prostaglandin E2. It has been found that the coated NCs significantly enhance cardiac function, inhibit cardiac remodeling, increase circulating myocardial cells, promote the activation of endogenous stem/progenitor cells, and stimulate angiogenesis. Targeted delivery of rapamycin using platelet membrane-coated PLGA nanoparticles has been employed to treat atherosclerotic plaques in ApoE-/- mice. The results show that the nanoparticles can specifically accumulate in atherosclerotic plaques, significantly reduce plaque area by inducing macrophage autophagy, and enhance plaque stability. Targeted nanoparticles not only enhance the anti-atherosclerotic activity of drugs but also reduce adverse reactions such as abnormal blood lipid levels caused by free rapamycin.

Furthermore, platelets play a role in hemostasis, clot formation, and are involved in coagulation-related diseases. Therefore, platelet membrane-coated biomimetic nanoparticles can be used to regulate clotting-related disorders. Treating immune thrombocytopenic purpura with platelet membrane-coated biomimetic nanoparticles has shown promising results. Due to the preservation of platelet surface proteins on the nanoparticles, they can specifically bind to anti-platelet antibodies, preventing the release of pathological antibodies and protecting normal circulating platelets, thus maintaining normal hemostatic function. These biomimetic nanoparticles exhibit high biocompatibility, have a long residence time in the body, and can be used as alternative targets for the treatment of diseases. Silica and platinum nanoparticles coated with platelet membranes have been modified to function as nanomotors carrying urokinase and heparin for targeted thrombolysis and anticoagulation therapy. Research has shown that the drug-loaded nanomotors can specifically accumulate at the site of thrombosis, penetrate into the thrombus, and significantly enhance thrombolysis. Platelet membrane-coated PLGA nanoparticles delivering streptokinase to the carotid artery thrombus have demonstrated high affinity to thrombus, superior thrombolytic effects, and significantly reduced bleeding risks.

Platelet membrane biomimetic nanocarriers can not only be used for treatment but also for disease diagnosis and integrated imaging therapy. By combining biomimetic nanocarriers with imaging probes, targeted enhanced imaging can be achieved. Platelet membrane-coated MRI (magnetic resonance imaging) contrast agents have been developed, and both in vitro and in vivo experiments have shown that the membrane-coated contrast agents exhibit high affinity to atherosclerotic plaques, providing sufficient contrast to distinguish the presence of plaques in real-time imaging. They can also target and visualize early-stage endothelial injuries caused by atherosclerosis, making them suitable for early disease prevention.

Compared to biomimetic nanoparticles derived from other cell membranes, platelet membrane biomimetic nanocarriers have the advantage of not only specifically adhering to damaged blood vessels but also actively targeting areas of vascular inflammation and injury. This enhances the efficacy of drugs, reduces adverse reactions from free drugs, and minimizes the accumulation of nanoparticles in healthy organ tissues.

3. Other Applications of Platelet Membrane Biomimetic Nanocarriers

Platelet membrane biomimetic nanocarriers have important research significance not only in oncology and cardiovascular diseases but also in other diseases. They have unique therapeutic applications in areas such as biodefense, bacterial infection treatment, gene silencing, and rheumatoid arthritis.

Researchers have synthesized platelet membrane nanomotors for the adsorption and separation of platelet-targeted biologics. Experimental findings indicate that these nanomotors exhibit strong affinity to platelet toxins and pathogens, selectively binding to Shiga toxin. This provides a new approach for biodefense and targeted treatment of infectious diseases. In a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection, platelet membrane-coated PLGA nanoparticles targeted delivery of vancomycin displayed superior therapeutic effects compared to the pure drug group and red blood cell membrane-coated nanoparticle group.

Platelet membrane-coated metal-organic framework nanoparticles have been employed for the delivery of siRNA to achieve targeted gene silencing in vivo. This approach has been used for the treatment of siRNA-related diseases such as tumors and thyroid hormone-mediated amyloidosis. Targeted delivery of FK506 using platelet membrane biomimetic nanocarriers has been shown to highly accumulate in inflamed synovial tissues and significantly control the progression of rheumatoid arthritis.

These applications demonstrate the versatility of platelet membrane biomimetic nanocarriers in various disease contexts. By leveraging the unique properties of platelets, such as their targeting abilities and interaction with pathogens, these nanocarriers hold great potential for advancing therapeutic interventions in diverse medical fields.

References:

[1] Xu, J., Xu, Q., Wang, X., et al. (2018). Research Progress on Platelet and Platelet Membrane-Based Biomimetic Drug Delivery Systems. Journal of China Pharmaceutical University, 49(6), 653-659.

[2] Lin, L., Chen, Y., Jin, Q., et al. (2021). Research Progress of Platelet Membrane Biomimetic Nanocarriers. Chinese Journal of Ultrasound in Medicine, 30(5), 5.