Delivery of TCM Monomers Using Blood Cell Membrane Coated Biomimetic Nanoparticles to Target CVD

Abstract

Cell membrane-coated nanoparticles are receiving increasing recognition for their potential in treating cardiovascular diseases (CVD). This novel drug delivery system, featuring drug-loaded nanoparticles modified by naturally derived cell membranes, is capable of precisely targeting diseased sites, improving drug bioavailability, evading immune surveillance, and prolonging half-life. These targeted and protective behaviors are driven by the preservation of functional surface proteins on the cell membrane, such as CD47 for inhibiting macrophage phagocytosis and specific integrins for targeting disease sites. More importantly, by translating inherent multi-target bioactivities into localized therapeutic outcomes, this biomimetic nanotechnology can significantly improve the drug delivery of TCM monomers, whose therapeutic effects on the treatment of CVD have been widely recognized. However, their clinical translations have historically been restricted by low bioavailability and unfavorable pharmacokinetics. Therefore, this review underscores recent developments in cell membrane-coated nanocarriers for treating CVD. It then highlights the application of traditional Chinese medicine (TCM) monomers delivered via cell membrane-coated nanoparticles in atherosclerosis, thrombosis, myocardial infarction, and ischemic stroke. Finally, this work discusses the challenges for clinical translation of these biomimetic nanocarriers by highlighting the technical complexities of source cell collection, membrane extraction efficiency, and large-scale manufacturing standardization that currently block clinical translation.

Graphical Abstract

Introduction

Cardiovascular diseases (CVD), which encompass atherosclerosis (AS), thromboembolism, myocardial infarction (MI), and ischemic stroke (IS), remain the most life-threatening conditions worldwide. Hence, there is an urgent need to decrease mortality and morbidity of CVD all over the world.

Traditional drug delivery approaches utilized “naked drugs”, which suffer from a wide range of deficiencies including rapid systemic clearance, lack of lesion-specific accumulation, and non-specific toxicities.¹ To address these limitations, nanoparticles have emerged as a novel drug delivery system which exhibit a multitude of strengths including precision lesion targeting, drug bioavailability improvement, and various functional payloads. However, engineered nanoparticles may also experience diminished biological activity, for the recognition and clearance by the mononuclear phagocyte system(MPS) can easily limit the effectiveness of these exogenous nanodrugs.² Among which, liver metabolism, rather than renal clearance, serves as the predominant elimination route for systemically administered nanoparticles.³ Representing 80–90% of all body macrophages, liver Kupffer cells can eliminate 30–99% of injected nanoparticles via three mechanisms, including Kupffer cell phagocytosis, fenestral uptake by liver sinusoidal endothelial cells, and hepatocyte endocytosis followed by biliary excretion.⁴ In contrast, renal clearance is severely restricted by the glomerular membrane’s size barriers, preventing nanoparticles smaller than 6 nm to pass.⁵

To overcome these biological barriers, cell membrane-coated biomimetic nanomedicine has gained considerable attention. By faithfully preserving the lipids, proteins, and carbohydrates of the source cells, these membrane-coated nanoparticles are endowed with high biocompatibility and motility, inherent biodegradability, exceptional circulation stability, and the capacity to traverse biological barriers.² In addition, they exhibit reduced immunogenicity, prolonged half-life, enhanced drug-loading capacity and targeting ability towards cells and tissues.⁶

Yet, conventional CVD drugs, such as antiplatelet agents, statins, and diuretics, may induce adverse effects affecting the cardiovascular, metabolic, and respiratory systems in patients. Thus, TCM has gained increasing attention in CVD therapy. Previous studies have found that Chinese medicinal herbs can be used as potential anticoagulants, for the active components extracted from them, such as Salvia miltiorrhiza, Scutellaria radix, Chuanxiong rhizoma, Persicae semen, Safflower, and Panax notoginseng, exhibit pronounced anticoagulant activities.⁷ This has indicated that these herbs hold promise as therapeutic agents for a range of CVD, including AS, thrombosis, MI, and IS. However, the clinical application of these promising TCM monomers is hindered by their poor water solubility, low bioavailability, and rapid clearance rate. Therefore, it is essential for us to explore the integration of TCM monomers with cell membrane-coated nanoparticle technology, which may enhance their targeting ability and safety profile while preserving therapeutic efficacy.

Although several excellent reviews have comprehensively summarized recent advances in cell membrane-coated nanotechnology and its applications in various diseases, including cancer, CVD and bacterial infections, none have specifically mentioned the integration of this technology with TCM monomers.^8–10 Furthermore, no existing review has systematically evaluated how membrane coating modifies the pharmacological effects of TCM monomers in the treatment of CVD. Therefore, our review aims to fill this gap by focusing on the mechanisms of TCM monomers that have already been incorporated into cell membrane-coated nanoparticles for the treatment AS, thrombosis, MI and IS. We have provided a systematic comparison of the pharmacological actions of these TCM monomers in the treatment of CVD. In addition, we critically analyze the changes in therapeutic efficacy, safety profile, and bioavailability of these TCM monomers before and after membrane coating. In the future perspective section, we explore the future of nanomedicine by integrating smart engineering and personalized biomimetic strategies while critically analyzing the barriers to clinical translation, such as manufacturing scalability, biological hurdles, and regulatory complexities.

The Preparation of Cell Membrane Nanoparticles

Cell membrane-coated nanoparticles typically consist of a nanoparticle core enveloped by a cell membrane, and the engineering process generally encompasses three key steps, namely cell membrane extraction, nanoparticle core fabrication, and membrane purification and coating. Among which, the commonly used nanoparticle cores can be classified into lipid-based nanoparticles, polymer nanoparticles, magnetic nanoparticles, and metal nanoparticles. The entire fabrication process of cell membrane nanoparticles is illustrated in Figures 1 and 2, while the functions of frequently utilized cell membranes are summarized in Table 1.

Figure 1.

Preparation of cell membrane nanoparticles.

Figure 2.

Methods used in cell membrane extraction and coating (Cell membrane extraction: (a) Repeated freeze-thaw; (b) Differential centrifugation; (c) Sucrose gradient ultracentrifugation; (d) Nitrogen cavitation; Cell membrane coating: (a) Mechanical extrusion; (b) Sonication; (c) Ultrasonication and extrusion; (d) Microfluidic electroporation).

Table 1.

The Functions of Various Cell Membrane

Function	Cell Membrane Type	Mechanism of Action	Application in Diseases	Refs
Immune Evasion & Prolonged Circulation	Platelet Membrane	-Bind to the SIRPα on macrophages:CD47 -Extend blood circulation to 30h	AS (ApoE−/−+HFD) Aortic valve (carotid artery ligation)	[11–13]
	RBC Membrane	-Bind to the SIRPα on macrophages:CD47 -Defend against complement system C2:C8bp, HRP, DAF, MCP, CR1, and CD59 -Extend circulation time to 36.5h	Ischemic myocardium (LAD ligation) AS (ApoE−/−+HFD)	[12,14–16]
	Macrophage Membrane	-Can be recognized as a “self” component -Extend circulation time to 8.38h	MIRI (LAD ligation) AS (ApoE−/−+HFD)	[17–19]
	Monocyte Membrane	-Bind to the SIRPα on macrophages:CD47 -Extend circulation time to 3.15h	AS (ApoE−/−+HFD)	[20,21]
	MSC Membrane	-Bind to the SIRPα on macrophages:CD47 -Extend circulation time to 24h	AS (ApoE−/−+HFD) IS (Rose Bengal injection) Pulmonary arterial hypertension (monocrotaline injection)	[13,22,23]
Targeted Delivery to Vascular/Inflammatory Sites	Platelet Membrane	-Adhere to exposed subendothelial extracellular matrix in damaged vasculature:GPIIb, GPIbα, and P-selectin	AS (ApoE−/−+HFD) IS (ligation of distal ECA)	[24–28]
	Macrophage Membrane	-Recruit to inflamed sites:C-C chemokine receptors -Adhere to activated endothelium:overexpress VCAM-1	Myocarditis (αMHC peptide injection) Sepsis-induced myocardial dysfunction (LPS, caecal ligation and puncture)	[29–33]
	Neutrophil Membrane	-Adhere to activated endothelium (ICAM-1, VCAM-1):integrin β2 -Penetrate into inflamed endothelial cells:leukocyte integrins (CD11a/CD18, Mac-1, VLA-4, PSGL-1)	MIRI (LAD ligation) IS (transient middle cerebral artery occlusion)	[34–38]
	Monocyte Membrane	-Penetrate into inflamed endothelial cells:downregulate VCAM-1, ICAM-1 -Target unstable plaque:interact with VCAM-1	IS (middle cerebral artery occlusion)	[20,39]
Anti-Inflammatory & ROS Scavenging Effects	Platelet Membrane	-Attenuate NETs and mitochondrial ROS scavenging:inhibit CD62P -Eliminate oxidative stress:decrease ROS level	MI (LAD ligation) IS (middle cerebral artery occlusion) Vascular restenosis (carotid artery injury)	[40–43]
	RBC Membrane	-Reduce proinflammatory cytokines:IL-12, TNF-α -Increase anti-inflammatory cytokines:IL-10	Carotid thrombus (FeCl3) AS (ApoE−/−+HFD)	[44–47]
	Macrophage Membrane	-Bind to and neutralize proinflammatory factors:TNFα, IL-1β, CXCL9 (CD80, CD86) -Increase anti-inflammatory cytokines:IL-10 and IL-4 (CD206, CD209, CD163)	IS (external carotid artery occlusion) Thoracic aortic dissection (BAPN)	[29–31,48,49]
	Neutrophil Membrane	-Polarize M1 macrophage to the M2 phenotype:phosphatidylserine -Degrade by lysosomes in macrophages:captured cytokines -Decrease inflammatory factors:NLRP3, TNF-α, IL-6, ASC	MI (LAD ligation) AS (ApoE−/−+HFD) IS (middle cerebral artery occlusion)	[50–54]

Cell Membrane Extraction

For a long time, commercial kits with detergents were the standard to solubilize proteins from the membrane. However, these detergents are challenging to eliminate and may compromise both the evaluation and stability of cell membrane nanoparticles. Moreover, the extraction process inevitably results in the loss of weakly bound lipids, cofactors, and protein‑protein interactions.⁵⁵ As one of the most widely employed techniques, differential centrifugation utilizes successive centrifugation steps at higher speeds to sequentially isolate cellular components according to their size and density. The low-speed spins can remove larger organelles like nuclei and mitochondria, thereby enriching the cell membrane fraction. Sucrose gradient ultracentrifugation provides a more sophisticated method for membrane isolation by employing a discontinuous density gradient to fractionate cellular components according to their buoyant densities. In contrast to differential centrifugation, which depends exclusively on variations in sedimentation rates, this technique enables more selective separation by allowing membranes to move to distinct density layers, thereby minimizing contamination from other organelles.⁵⁶ Ultrasonic and mechanical homogenization have also been extensively used in cell membrane extraction. In contrast to the two methods mentioned above, which may cause protein aggregation, nitrogen cavitation imposes significantly less chemical and physical stress on enzymes and subcellular compartments.⁵⁷ The repeated freeze-thaw procedure primarily involves freezing at −80 °C, thawing at room temperature, and collecting the pellet via centrifugation.⁵⁸ Comparatively, it has simplified the operation process, therefore making it another commonly used method for cell membrane extraction. To better elevate productivity, researchers have turned to developing another novel strategy for cell membrane extraction, namely nitrogen cavitation. Employed for cell homogenization since the 1960s, nitrogen cavitation enables rapid cell disruption while preserving the biological functions of membrane antigens. The underlying mechanism involves dispersing nitrogen within cells under high pressure in a sealed vessel. Upon rapid pressure release, nitrogen exits the solution and forms bubbles intracellularly, and these bubbles expand, rupturing the cell wall and swiftly releasing cellular contents. Concurrently, the plasma membrane spontaneously generates numerous vesicles.⁵⁹ However, this separation approach is relatively expensive and demands a large number of cells. Therefore, to adapt this classical technique to meet the current demands of processing small-scale samples, Zhou et al developed a modified nitrogen cavitation protocol. Following nitrogen cavitation, the homogenate is fractionated into soluble and membrane components via differential centrifugation. This involves an initial low-speed centrifugation step to eliminate nuclei and unbroken cells, followed by a high-speed centrifugation step (>100,000 g) to isolate membranes from the soluble components.⁶⁰

The cell membrane extraction methods, along with their respective advantages and limitations, and their applications are listed in Table 2.

Table 2.

The Applications and Advantages of Nanoparticle Cores

Nanoparticle Type	Application	Advantage	Refs
Lipid-based nanoparticle	- mRNA drug delivery - AS treatment - CRISPR gene editing in the liver - IS treatment	- Enhanced cellular uptake and endosomal escape - Structural stability - Inhibited vesicle aggregation and MPS clearance	[61–64]
Polymeric nanoparticle	- Aortic injury treatment - Atherosclerosis - Vascular dysfunction - Cardiac injury	- Minimal toxicity (FDA approval) - Sustained drug release and targeted distribution - Enhanced oral bioavailability	[19,65–69]
Magnetic nanoparticle	- MRI contrast agent (plaques, infarcted heart) - Magnetic targeting carriers - Thrombolytic drug delivery	- Superparamagnetic and magnetic-responsive properties - Immune and inflammatory cell recognition - High capture efficiency - Low manufacturing cost and high bioavailability	[70–74]
Silver nanoparticle	- Healthcare and consumer products - Antithrombotic drug delivery	- Antibacterial activity - Anti-inflammation - Antiplatelet property	[75]
Gold nanoparticle	- Contrast agents (plaques, thrombi, fibrotic tissue) - Drug carrier	- Large surface area - Antioxidant and anti-inflammatory features - High biosafety - Simple synthesis and controllable size	[76,77]
MSN nanoparticle	- Controlled drug release	- Dual-surface functionalization - Minimized aggregation and enhanced stability - Stimuli-responsive release	[78,79]

Nanoparticle Core Fabrication

Lipid-Based Nanoparticle

Lipid-based nanoparticles, widely used in mRNA drug delivery, consist of four key components: an ionizable lipid, cholesterol, a helper phospholipid, and a lipid-anchored polyethylene glycol (PEG) conjugate. The ionizable lipid facilitates cellular uptake and endosomal escape, while cholesterol and helper phospholipids such as DOPE provide structural stability to the lipid bilayer.⁶¹ The PEG-lipid conjugate inhibits vesicle aggregation and evades clearance by the MPS, thereby extending systemic circulation. These structural features endow lipid nanoparticles with unique advantages. Their small size allows them to easily penetrate tissues and cells, while their protective shell shields encapsulated drugs from enzymatic and chemical degradation. In AS treatment, these nanoparticles exhibit specific clearance affinity towards low-density lipoprotein(LDL) by binding to endogenous apolipoprotein E (ApoE) in the liver, which subsequently interacts with LDL receptors on hepatocytes.⁶² Their therapeutic potential is further demonstrated in applications such as CRISPR gene editing, where lipid nanoparticles yielded around 35% editing efficiency in the liver and markedly decreased serum ANGPTL3, LDL-C, and TG levels sustained for up to 100 days.⁶³ In IS, anti-inflammatory drugs, including interleukin-10 mRNA and dexamethasone, reduced cerebral infarct volume by 62% and 35%, respectively, only when encapsulated in lipid nanocarriers.⁶⁴ Additionally, these nanoparticles enable controlled drug release through surface functionalization with ligands or other modifications. A variety of techniques are available for formulating lipid nanoparticles, including solvent emulsification-diffusion, solvent evaporation, microemulsion, double emulsion, high-pressure homogenization, ultrasonication, and high-speed homogenization.

Polymeric Nanoparticle

Polymeric nanoparticles, measuring 10 to 1000 nm in diameter, are derived from natural or synthetic polymers, with biodegradable poly(lactic-co-glycolic acid) (PLGA) being the most prevalent due to its high biosafety. PLGA is hydrolyzed in vivo to yield lactic acid and glycolic acid, both of which are endogenous metabolites that are easily processed via the Krebs cycle, therefore resulting in minimal systemic toxicity and leading to its FDA approval as a pharmaceutical excipient.⁶⁵ Its high biocompatibility makes PLGA a frequent choice for delivering therapeutic substances. In a rat model of inferior vena cava patch venoplasty, PLGA-rapamycin nanoparticles demonstrated sustained drug release plateauing by day 15, indicating a delivery duration of at least two weeks.⁶⁶ Similarly, PEG-PLGA encapsulation of isoliensinine reduced its in vivo clearance rate from 36.07 ± 6.6 to 12.62 ± 4.02 L/h/kg and achieved five-fold higher organ accumulation compared to the free drug, demonstrating improved pharmacokinetics and targeted distribution. PLGA nanoparticles also enhance the oral bioavailability of poorly soluble drugs. For instance, PLGA-encapsulated rivaroxaban exhibited a sustained release rate of 97.64% after 48 hours, compared to 68.45% for the bare drug.⁶⁷ However, the lipophilic nature of PLGA can lead to non-specific recognition and clearance by the MPS, reducing mitochondrial accumulation and potentially impairing immune function.⁸⁰

Magnetic Nanoparticle

Owing to their superparamagnetic and magnetic-responsive properties, magnetic iron oxide nanoparticles are highly regarded as magnetic resonance contrast agents and magnetic targeting carriers for CVD imaging, diagnosis, and drug or gene delivery. These nanoparticles can be bound to cell surfaces via antibodies or ligand-receptor pairs, enabling cell retention under shear stress. They can also be internalized into cells, making them responsive to magnetic fields while being biodegradable and biocompatible.⁷⁰ Their selective recognition of immune cells and inflammatory vascular cells has resulted in broad application across a range of diseases. Computational modeling using a Circle of Willis (CoW) system demonstrated that magnetic particle capture efficiency decreases with particle diameter, with particles larger than 2 μm achieving up to 98% capture efficiency at targeted locations, supporting magnetic drug targeting as a viable CVD treatment strategy.⁷¹ Magnetic nanoparticles extend the half-life of thrombolytic drugs from 19.7 to 59.9 minutes and serve as effective angiography agents due to the excellent imaging characteristics and safety profile of Fe₃O₄. These nanoparticles show increased extravasation and macrophage uptake at sites of inflammation, such as atherosclerotic plaques or infarcted heart tissue, where they accumulate in endo-lysosomes and release their iron oxide cargo upon coating degradation, enabling site-specific CVD imaging.⁷² To achieve more precise delivery, a magnetizable stent positioned at a diseased carotid artery can produce localized magnetic field gradients that guide magnetically responsive drug carriers while limiting field exposure to surrounding tissues.⁷³ Despite advantages including low manufacturing cost and high bioavailability, magnetic nanoparticles pose cytotoxic risks by promoting coagulation, inducing cardiac oxidative stress within 24 hours of injection, and causing oxidative cardiomyocyte degeneration and cardiac dysfunction within 30 days. They can also induce HUVEC apoptosis and, in AS treatment, promote plaque vulnerability and increase aortic plaque area by inhibiting nitric oxide production and endothelial nitric oxide synthase (eNOS) activity.⁷⁴

Metal Nanoparticle

Silver Nanoparticle

Silver nanoparticles are widely incorporated into healthcare and consumer products for their antibacterial properties, which arise from the ionization of metallic silver in aqueous environments to release Ag⁺ ions that bind to sulfhydryl groups and protein residues on cell membranes. By inhibiting the secretion of inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), IL-6, and IL-8, these nanoparticles exert anti-inflammatory effects and demonstrate antiplatelet activity by accumulating in platelet granules and inhibiting integrin-mediated platelet adhesion, making them useful for antithrombotic drug delivery.⁷⁵ However, silver nanoparticles also induce toxicological effects, including inflammation, oxidative stress, apoptosis, and gene expression changes in animal cells. In zebrafish embryos, acute exposure causes cardiotoxicity by upregulating cardiac development genes, while in cardiac cells, they produce reactive oxygen species (ROS) and trigger autophagy and cell death mediated by mitochondrial dysfunction.⁸¹ Furthermore, silver nanoparticle exposure can trigger neurotoxicity by upregulating proteins associated with neurodegenerative disorders and downregulating those responsible for brain homeostasis, with inflammatory pathways significantly upregulated at 24 hours and blood-brain barrier (BBB) damage-related proteins upregulated at 48 hours post-exposure.⁸²

Gold Nanoparticle

Gold nanoparticles, including various forms such as nanorods, nanocages, and nanoshells, possess exceptional bio-optical properties like surface plasmon resonance that enable their use as contrast agents for detecting atherosclerotic plaques, intravascular thrombi, and fibrotic tissue. Their large surface area and high surface activity make them excellent drug carriers capable of loading diverse molecules, including drugs, nucleic acids, proteins, and targeting ligands, while their inherent antioxidant and anti-inflammatory features enhance therapeutic efficacy.⁷⁶ Gold nanoparticles demonstrate high biosafety due to their inertness and low toxicity, and their simple synthesis and controllable size fabrication make them suitable for various biomedical applications. In animal models of inflammation, gold nanoparticles reduce oxidative tissue damage by decreasing ROS and nitrogen species production, improving antioxidant activity, and downregulating pro-inflammatory cytokines, specifically TNF-α, IL-1β, and IL-6.⁷⁷ Studies have demonstrated that gold nanoparticles selectively accumulate in the heart and vasculature during disease states, making them promising drug carriers for CVD.

Mesoporous Silica Nanoparticle (MSN)

MSNs have gained attention since the synthesis of MCM-41 in 1992. With an inner cylindrical pore and an outer particle surface, MSNs can facilitate coupling with various functional compounds. Surface functional groups enable control over pore entrance size for molecule entrapment, minimizing particle aggregation and enhancing stability and redispersion. The customizable pore size allows MSNs to encapsulate high payloads of diverse agents while maintaining drug stability during transit to the site of action. Their large specific surface area and honeycomb-like porous structure confer high drug loading capacity, easy surface modification, and superior thermal and chemical stability.⁷⁸ MSN fabrication is mainly conducted by two methods. The liquid crystal templating precipitates silicates onto cylindrical organic structures, while the cooperative self-assembly requires negative charges supplant surfactant counterions to facilitate mesophase assembly.⁸³ In drug delivery systems, MSNs allow for controlled drug release exclusively in response to external or internal stimuli such as light, magnetic fields, pH changes, enzymes, or redox species.⁸⁴ Despite these advantages, no silica-based nanocarrier has reached clinical application due to challenges in reproducibility and industrial scalability, as maintaining consistent particle size, pore size, and volume during large-scale manufacturing remains difficult. Biosafety concerns also persist, for large SBA-15-type MSNs can induce red blood cell membrane deformation and hemolysis, while other MSN formulations may promote human malignant melanoma cell proliferation by inhibiting NF-κB activation and upregulating Bcl-2 expression through oxidative mechanisms.⁷⁹

The advantages of these nanoparticle cores and their applications in CVD are listed in Table 3.

Table 3.

Extraction Methods of Cell Membrane

Extraction Method	Membrane Type	Advantages	Disadvantages	Refs
Nitrogen cavitation	Neutrophil membrane	Engineer controllable and synthesizable membrane nanovesicles without genetic materials, overcome scalability, reproducibility, and heterogeneity	Expensive; require a large number of cells	[59,60,85]
Hypotonic lysis	K562 cell membrane	Fast, scalable, reproducible, and detergent-free, stable cell membrane index	Require a sufficient number of cells	[55]
Protein extraction kit	Macrophage membrane	Standardized and commercial	May compromise protein structure and functionality	[86]
Mechanical homogenization	Plasma membrane	Intact membrane-bound proteins	Typically requires integration with other methods to isolate the fragments	[87]
Sonication	Platelet membrane	Simple to use; protects samples from shear and oxidation; lowers viscosity	Inadequate for complete proteome lysis, lead to localized heating, mechanical shear, oxidative damage, and free radical generation	[88,89]
Freeze-thaw	Platelet membrane	Technical simplicity; effectively retain functional membrane proteins; wide applicability and good repeatability	Insufficient cell sources, long-term storage	[58]
Differential centrifugation	RBC membrane	Simple, accessible, process large volumes of cells, high yield	Impair membrane integrity, denature proteins, and compromise functional receptors	[90]
Sucrose gradient ultracentrifugation	Macrophage membrane	Produces highly pure membrane fractions with minimal nuclear and cytoplasmic contamination; preserves functional membrane proteins; well-suited for comparative studies and large-scale research	Demands more time and labor, expensive but lower yield, structural alterations in certain membrane proteins	[91]

Cell Membrane Coating

Several approaches exist for coating nanoparticle cores with isolated membrane fragments, among which extrusion and sonication are the most common. The sonication process typically utilizes a bath sonicator, while the extrusion method requires passing the fragments through polycarbonate porous membranes.⁹² Relevant studies have also indicated that the combination of sonication, extrusion, and ultrafiltration has been employed in cell membrane coating. In electroporation, applied electric fields destabilize the dielectric layer over cell membranes, inducing the formation of transient pores for the entry of biomolecules and nanoparticles. Since their introduction in 2001, microfluidic devices have established themselves as a promising platform for the fabrication of versatile nanomaterials, leveraging benefits such as high throughput, quantitative capabilities, and parallel scalability.⁹³ The methods used for the coating of cell membranes onto the nanoparticle core, their advantages and disadvantages, and their applications are listed in Table 4.

Table 4.

Coating Methods of Cell Membrane

Membrane	Cell Membrane Coating	Advantages	Disadvantages	Refs
RBC membrane	Ultrasonication and extrusion	Resolve broad particle size distribution, inadequate particle coating, and heterogeneous lipid shells; bypass the time-consuming procedures of protein identification, purification, and conjugation;preclude chemical modifications that could compromise target protein structural integrity and biological functions	The mechanical extrusion process can result in the depletion of peripheral membrane proteins associated with spectrin cytoskeletal proteins; challenges in clinical translation; destroy the nanoparticle core	[94]
RBC membrane	Mechanical extrusion	Retain almost all the membrane proteins; precise control and consistent reproducibility	Requires prohibitively large forces	[47]
Plasma membrane	Sonication	Increased yield with minimal material loss; technical simplicity; autonomous integration of nanoparticles with membrane vesicles	Increased temperatures, unstability	[95]
Cancer cell membrane	Microfluidic electroporation	Integrality of membrane structure, more functional proteins, universal for varies nanoparticles or cells; completer cell membrane coating and better colloidal stability; multiplexed reaction integration on a single microfluidic chip, facilitating expedited core–shell nanoparticle assembly; superior coating efficiencies (reaching 93%)	Inadequate membrane disruption by hydrodynamic forces alone within microfluidic channels	[93,96,97]

After membrane coating, the obtained nanoparticles also need the characterization process to ensure that they have been successfully wrapped. The hydrodynamic size, polydispersity index (PDI), and zeta potential of the nanoparticles were determined using dynamic light scattering (DLS). Transmission electron microscopy (TEM) was employed to permit clear observation and recording of the nanostructure, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was conducted to analyze the membrane proteins. Encapsulation efficiency (EE) and loading efficiency (LE) were assessed via fluorescence intensity measurement. Furthermore, particle size during storage, an indicator of RBC nanoparticle stability, was monitored.⁹⁸

Cell Membranes Commonly Used in the Treatment of CVD

Unprotected drug-loaded nanoparticles suffer from limitations, including rapid recognition and clearance by the MPS, leading to their swift elimination from the body, which is a shortcoming that can be addressed through the use of cell membrane-coated nanoparticles.

Platelet Membrane

Platelets, often produced by megakaryocyte progenitor cells, are 2–3 µm in diameter and typically live for 5–9 days. A range of specific membrane proteins associated with activated platelets, including GPIIb, GPIbα, and P-selectin, are present on these structures. These proteins allow platelets to dynamically adhere to the subendothelial extracellular matrix exposed at sites of vascular injury. The hemostatic properties of platelets arise from their ability to co-localize with von Willebrand factor (vWF), collagen, and fibrin within injured blood vessels.²⁴ Moreover, platelets express CD47, a cell-surface glycoprotein that interacts with the inhibitory receptor SIRPα on macrophages. This interaction suppresses macrophage activation and phagocytosis, allowing nanoparticles to evade immune clearance and achieve prolonged circulation in the blood.¹¹ The interactions between platelets and immune cells have also been pivotal. Studies have found that platelets can markedly attenuate neutrophil extracellular traps (NETs) generation and mitochondrial ROS scavenging in neutrophils via inhibiting CD62P signaling. In addition, platelets contribute to the inflammatory response by recruiting inflammatory cells to lesion sites and releasing a wide array of inflammatory mediators, thereby intensifying the local inflammatory milieu.⁴⁰ This targeting capability enables platelets to specifically interact with various cell types, such as endothelial cells, circulating leukocytes (monocytes, neutrophils, dendritic cells, and T-cells), and progenitor cells, making them attractive candidates for specific drug carriers.

With minimum systemic cytotoxicity, platelet membrane has been proposed as a potential camouflager. Through mimicking cellular functions, these nanoparticles can enhance treatment efficacy. In vivo studies have demonstrated that platelet membrane coating can extend drug circulation duration to 30 hours by capitalizing on the unique properties of platelets. A key advantage of these nanoparticles is their ability to achieve both passive and active targeting, with active targeting mediated by membrane moieties that bind to protein receptors overexpressed on target cells or tissues.⁹⁹ The platelet membrane also excels at reducing oxidative stress, for in the treatment of IS, it was shown to reduce ischemic area by 63% and ROS levels by 72% compared to free drug administration. Additionally, the coating enhances the colloidal stability of nanoparticle cores, which would otherwise become unstable and aggregate under physiological salt concentrations.¹⁰⁰

RBC Membrane

Erythrocytes (red blood cells, RBCs) constitute the predominant population of circulating cells in the bloodstream. With the structure of being anucleated and organelles lost during maturation, their shape and volume can undergo a number of reversible transformations, thereby rendering them effective vehicles for the delivery of various bioactive compounds, such as enzymes, drugs, proteins, and macromolecules.¹⁰¹ The long circulation time of RBCs, ranging from 100 to 120 days, is facilitated by multiple membrane proteins expressed on their surface. CD47 functions as a self-marker that actively signals macrophages to prevent erythrocyte uptake, and in addition, other membrane proteins on the RBC surface can also contribute to defending against complement system attacks. These include C8 binding protein (C8bp), homologous restriction protein (HRP), decay accelerating factor (DAF), membrane cofactor protein (MCP), complement receptor 1 (CR1), and CD59.¹⁴

RBC membrane-derived nanoparticles have been extensively employed as drug delivery vehicles for the treatment of various diseases. One of the earliest examples dates back to 1973, when Ihler et al successfully immobilized various enzymes onto the RBC membrane. As a kind of natural “innate carrier” to decorate artificial nanoparticles, RBC membranes have the benefits of extending circulation time, improving membrane flexibility and stability, enhancing biocompatibility, and maintaining functional groups for further modification.¹⁰² It has been estimated that nanoparticles with RBC membrane coating can extend the circulation time to 36.5 hours and increase uptake by approximately 40 times compared to uncoated nanoparticles. This enhanced performance holds promise for applications in drug delivery and magnetic resonance imaging (MRI). RBC coating also helps prevent the nanoparticles from clearance of the immune system. In a study incubating macrophages and RBC membrane nanoparticles, the fluorescence of bare nanoparticles are much more stronger than RBC membrane-coated nanoparticles, proving that RBC membrane prevents the nanoparticles from degradation by the immune system.¹² One notable advantage of RBC membranes is their ability to reduce inflammatory and foreign body responses to nanoparticles, thereby enhancing biocompatibility. In a study by Fan et al, RBC membrane coating was found to downregulate IL-12 and TNF-α expression while upregulating IL-10 expression. It also increased the monocyte/macrophage percentage (28.15 ± 1.39%) and cell count (0.26 ± 0.04 million per scaffold), restoring these metrics to levels comparable to those without nanoparticles.⁴⁴ Given these advantageous properties, a growing number of studies have focused on the combined application of RBC membranes and platelet membranes for nanoparticle camouflage.

Macrophage Membrane

Originated from leukocytes in bone marrow, macrophages are differentiated from monocytes recruited from circulating blood, and have played a key role in mediating inflammation and tissue repair. They have a long life span, for in the human body, they can live up to several months or more.¹⁰³ Macrophages can be classified into two phenotypes: M1 and M2. The M1 phenotype is defined by surface markers CD80 and CD86, along with the release of proinflammatory cytokines and chemokines, including TNF-α, IL-1β, and CXCL9. Conversely, the M2 phenotype is marked by surface markers such as CD206, CD209, and CD163, and is associated with increased production of IL-10 and IL-4, suggesting a role in targeting inflamed sites.¹⁷ During infection or tissue injury, cytokines like C-C chemokine receptors further recruit macrophages to inflamed sites, as the cytokine receptors on macrophage surfaces can bind to and neutralize proinflammatory factors.²⁹

Through the inheritance of surface protein profiles and biointerfacing properties from source cells, macrophage membranes are equipped with a variety of surface receptors, enabling nanoparticles to move freely in the body. The immune system recognizes the macrophage-like membrane as a “self” component, thus protecting the loaded contents from being eliminated by the MPS and immune surveillance.¹⁷ Pharmacokinetics studies have indicated that macrophage membrane can extend the body circulation time of therapeutic agent from 1.51 h of free drugs to 8.38 h. Moreover, at 6 h post injection, 77.15% of membrane-coated nanoparticles still exist in the blood, in contrast to just 47.77% of drug-loaded nanoparticles and almost 0% of naked drugs. Furthermore, the macrophage membrane acts as a barrier that retains the loaded drug, preventing its leakage and premature release until uptake by cells occurs, and it also promote the cellular uptake of these nanoparticles.¹⁰⁴ Equipped with enhanced targeting ability, these nanoparticles can reach atherosclerotic plaques through specific phagocytosis by activated endothelium and overexpressing vascular cell adhesion molecule-1 (VCAM-1) on its surface, thus enabling the nanoparticles to attach to injured vessels. Evidence also supports that macrophage membrane coating enhances drug biosafety. For instance, in a study utilizing macrophage membrane nanoparticles for glioblastoma therapy, the coating was found to limit nanoparticle accumulation in primary organs in vivo, thereby mitigating nonspecific toxicity and adverse effects.¹⁰⁵

Neutrophil Membrane

Neutrophils are the predominant immune cells in the human body, making up 50–70% of all white blood cells.¹⁰⁶ To reach sites of inflammation, neutrophils migrate across blood vessel walls. During this process, circulating neutrophils first adhere to activated endothelium via membrane adhesion proteins, including integrin β2 on neutrophils and ICAM-1 and VCAM-1 on endothelial cells. They subsequently roll and crawl along the vessel lining. This motion enables neutrophils to encounter overexpressed chemokines on stressed vascular endothelial cells, thereby triggering their activation. With the help of several leukocyte integrins, namely lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (Mac-1), very late antigen-4 (VLA-4) and p-selectin glycoprotein ligand-1 (PSGL-1), neutrophils can adhere to and penetrate inflamed endothelial cells, therefore reaching inflammatory sites. This process can be completed within hours.³⁴ In addition to inflammation targeting, neutrophils themselves exhibit inherent anti-inflammatory properties. After reaching inflammatory lesions, activated M1 macrophages phagocytose neutrophils. The phosphatidylserine exposed on the neutrophil membrane then promotes the polarization of M1 macrophages to the M2 phenotype. Meanwhile, lysosomes within macrophages degrade cytokines and chemokines captured by nanoparticles, resulting in decreased expression of inflammation-related molecules, including IL-6, TNF-α, apoptosis-associated speck-like protein containing a CARD(ASC), and NOD-like receptor family pyrin domain containing 3(NLRP3).⁵⁰ During inflammation, neutrophils readily produce extracellular reticular structures called NETs, which consist of histones, granular proteins, and fragmented genomic DNA. NET formation releases various signaling factors and recruits additional immune cells to facilitate immune regulation and tissue repair, thereby accelerating the targeting ability of immune cell membrane-coated nanoparticles.¹⁰⁷ Neutrophils are also critically involved in the development and treatment of MIRI and IS, as they can penetrate the blood-brain barrier and accumulate over long periods.

Key proteins from the neutrophil membrane, including integrin α9, integrin β1, lymphocyte function-associated antigen-1 (LFA-1), P-selectin glycoprotein ligand-1 (PSGL-1), hyaluronic acid(HA), C-X-C chemokine receptor type 2 (CXCR2), and C-C chemokine receptor type 2 (CCR2), can be successfully retained on neutrophil membrane-coated nanoparticles.¹⁰⁸ The bioavailability and biosafety of certain drugs can also be improved by the neutrophil membrane. The area under the curve(AUC) of neutrophil membrane-coated nanoparticles was 18.02, compared with 14.94 of naked nanoparticles. Furthermore, the hemolysis rate induced by neutrophil nanoparticles was measured at 2.47%, showing no statistically significant difference compared to the negative control.¹⁰⁹ The application of neutrophil membrane coating also serves to improve the water solubility of particular drugs, for Zhang et al have proved that neutrophil membrane coating can significantly enhance water solubility from 0.03 mg/L to 5 mg/L.⁵¹ Relevant studies have also found that since they share the same membrane protein, neutrophil membrane nanoparticles can act as competitors for neutrophil membranes, therefore disrupting the connection between neutrophils and other inflammatory cytokines or receptors.

Monocyte Membrane

Representing 2–8% of circulating leukocytes and having a half-life of 1–3 days, monocytes are promising precursors for cell-derived nanovesicles. Their innate ability enables them to migrate to inflamed tissues within hours of activation, where they participate in antigen presentation, phagocytosis, and cytokine production.¹¹⁰ Shi et al demonstrated that monocyte membrane-coated particles exhibited prolonged circulation (T₁/₂ ≈ 3.15 h, more than five times longer than uncoated drugs) and enhanced accumulation in inflammatory sites via chemotactic signals, while their immune-evasive properties reduced uptake by resident macrophages.²⁰ In AS, monocyte membrane-coated nanoparticles show lower lysosomal colocalization, indicating improved endosomal escape and extended therapeutic action, and enabling specific delivery to inflamed endothelial cells over plaque tissues rather than quiescent endothelium.¹¹¹ In another study, monocyte membrane-coated rapamycin significantly reduced proliferating macrophage populations in aortas (15.6 ± 9.79%) compared to untreated (30.2 ± 13.34%) or rapamycin-alone groups (26.8 ± 9.87%). Moreover, monocyte membrane-coated nanoparticles decreased plaque area by 14.4 fold and foam cell percentage by 1.4 fold compared to the positive control group, while also attenuating key inflammatory factors (C1, C3, NLRP3, IL-1β, IL-18) more effectively than bare nanoparticles.¹¹² For MI, Chen et al engineered monocyte membrane-modified cardiac-resident macrophage extracellular vesicles (MmEVs) that exploit CD47 for immune evasion and monocyte membrane proteins for CCL2-mediated targeting to damaged cardiac regions, offering a cell-free alternative to macrophage transplantation. Additionally, monocyte membrane coating enables precise targeting to unstable plaque regions by interacting with VCAM-1, which promotes leukocyte infiltration and plaque vulnerability.³⁹

Microglia Cell Membrane

Comprising 10–12% of brain cells, microglia serve a dual function in neuroinflammation. At rest, they maintain brain homeostasis via phagocytosis of pathogens and debris, synaptic pruning, and secretion of neurotrophic factors including BDNF and IGF. When activated, they release pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and cytotoxic molecules that worsen neuroinflammation.¹¹³ In IS, microglia rapidly proliferate and dominate the lesion site by initially adopting an amoeboid phenotype that facilitates phagocytosis and neurotrophic release. But later, they shift to a neurotoxic state characterized by pro-inflammatory cytokine, ROS, and nitric oxide(NO) production, which hinders tissue repair. Toll-like receptor 4 (TLR4) serves as a critical mediator of inflammation that is modulated by the cholesterol content in lipid rafts, and microglia can clear pathological α-synuclein via TLR4–NF-κB–p62-mediated autophagy, therefore alleviating neurodegeneration.¹¹⁴ Microglia membrane-coated nanoparticles enhance homologous targeting to inflammatory sites, improving drug delivery and therapeutic efficacy. In acute IS, microglia membrane-coated nanoparticles loaded with anti-RGMa and sensitive to both low-intensity focused ultrasound (LIFU) and magnetic fields can disrupt thrombi via phase transition and cavitation, while specifically targeting brain microvascular endothelial cells and accumulating in embolic areas. The probable cause is the increased expression of metalloproteins, ROS, VEGF, and pro-inflammatory cytokines within activated perithrombotic microglia.¹¹⁵ M2-polarized microglia inherently release anti-inflammatory cytokines such as IL-10, TGF-β, Arg-1 and CD206, conferring neuroprotective and targeting properties in ischemic regions. For instance, M2 microglia membrane-coated nanoparticles inhibit NF-κB p65 activation by scavenging ROS, thereby suppressing pro-inflammatory microglial polarization, enhancing BBB penetration, increasing neuronal cell survival by 40%, and promoting functional recovery after stroke.¹¹⁶ Furthermore, nanoparticles coated with microglia cell membrane influence the bioactivity of other types of cells. For instance, bioorthogonal metabolic glycoengineering of MSCs with microglia membrane-coated nanoparticles creates a “micro-livable niche” by modulating ROS and oxidative stress, transforming the infarct milieu into a regenerative environment and boosting MSC viability approximately fivefold.¹¹⁷

Mesenchymal Stem Cell Membrane

For the past two decades, mesenchymal stem cells (MSCs) have become a promising therapeutic option due to their immunomodulatory, regenerative, and multipotent characteristics. They can be derived from bone marrow, umbilical cord, or adipose tissue.¹¹⁸ Part of their therapeutic potential stems from membrane proteins such as CXCR4, VLA-4, and CD47. VLA-4 facilitates MSC migration to injury sites via vascular endothelium, enabling MSC membrane-coated nanoparticles to traverse the BBB. CD47, on the other hand, inhibits phagocytosis by macrophages, thereby extending circulation time and improving treatment efficacy.

In CVD therapy, MSC-based strategies show promising targeting and therapeutic effects. In MI models, glucose-modified gold nanoparticles labeling MSC exosomes demonstrated specific retention in the infarcted myocardium for up to 24 hours with minimal off-target accumulation. MSC membrane camouflage on nanoparticles reduced macrophage uptake by 68%, enhanced circulation time, promoted endosomal escape for improved miRNA delivery, and increased cardiomyocyte numbers and contractility while offering cryopreservation stability.¹¹⁹ Notably, the therapeutic efficacy of MSCs is largely due to their paracrine actions via factors such as SDF-1, Ang-1, and VEGF-α, rather than direct myocardial engraftment, as observed in studies where BMSC-seeded patches exerted protective effects via epicardial deposition.¹²⁰ Additionally, MSCs can reduce cardiac fibrosis by secreting hepatocyte growth factor (HGF), which in turn activates MMP-2 and MMP-9 to degrade extracellular matrix components. It can also inhibit AS by decreasing macrophage oxidized LDL (ox-LDL) uptake, preventing the formation of foam cells, and enhancing endothelial repair through diminished expression of adhesion molecules including E-selectin, ICAM-1, and VCAM-1.¹²¹

MSCs have also been instrumental in the treatment of AS. To improve targeting, hybrid platforms combining MSC membranes with other cell membranes have been developed. For instance, leveraging natural cell homing mechanism, MSC membranes fused with platelet membranes yielded exosome-mimicking vesicles (MSC-ExoP) that co-expressed platelet and exosome markers, demonstrating superior performance compared to single MSC membranes. It facilitated cholesterol efflux and lowered cholesterol levels within foam cells by upregulating transporters ABCA1 and ABCG1, without adversely affecting serum lipid levels or major organ safety.²⁵ Similarly, engineered hybrid nanosystems, such as exosome-liposome fusions loaded with therapeutic polysaccharides, can attenuate neuroinflammation and restore lipid metabolism via pathways like AKT/Nrf2/HO-1, illustrating the versatility of MSC-based delivery platforms.¹²²

Hybrid Cell Membrane

Hybrid membrane nanoparticles integrate the beneficial features of distinct cellular membranes, such as targeted adhesion, long circulation, immune evasion, and immunomodulation, providing a versatile platform for treating inflammatory and ischemic CVD. Platelet membranes are frequently fused with other membranes to enhance vascular targeting. For example, platelet–M2 macrophage extracellular vesicle hybrids utilize platelet glycoproteins like GPIbα to specifically bind macrophages in atherosclerotic plaques under oxLDL stimulation while delivering anti-inflammatory miRNAs.¹²³ Similarly, platelet–mesenchymal stem cell exosome-mimetic nanovesicles leverage platelet adhesion proteins (GPIbα, GPVI) to target injured endothelium and collagen, promoting cholesterol efflux in foam cells.¹³ Combining platelet with erythrocyte membranes merges the inflammatory targeting of platelet proteins (CD62P, CD61) with the long-circulating “don’t eat me” property conferred by erythrocyte CD47, thus improving monocyte targeting in AS and reducing non-specific uptake.¹²⁴ For cardiac fibrosis, platelet–erythrocyte hybrids exploit GPIIb/IIIa and GPVI for collagen targeting and CD47 for immune evasion, enhancing antifibrotic drug delivery.¹²⁵ Immune cell membrane hybrids also offer unique advantages, for neutrophil–macrophage hybrids combine early injury-homing (via integrins ITGA5/ITGB1) with regulatory functions for targeted myocardial delivery. In myocarditis, T lymphocyte–macrophage hybrids present chemokine receptor CXCR3 and integrins for dual-targeting to inflamed myocardium, enabling efficient siRNA delivery to pro-inflammatory macrophages.¹²⁶ In stroke therapy, platelet–neutrophil hybrid liposomes employ platelet P-selectin for neutrophil hijacking and neutrophil cytokine decoy receptors to neutralize neuroinflammation.³⁵ More complex multi-membrane systems include platelet–microglial hybrids that combine vascular targeting (P-selectin) with cellular targeting (CX3CR1) for enhanced accumulation in injured brain tissue.¹²⁷ Macrophage–liposome hybrids modified with hyaluronic acid utilize macrophage membranes for immune evasion and HA for CD44 targeting on plaque macrophages, enabling dual-targeted drug delivery in AS.¹²⁸

Engineered Cell Membrane

Engineered cell membrane nanoparticles have become a promising therapeutic platform enabling targeted intercellular communication, though their inherent limitations, such as restricted natural bioactivity and lack of precise targeting, have motivated the development of advanced engineering strategies.¹²⁹ These approaches encompass lipid insertion, membrane fusion, genetic modification, and metabolic engineering, which are employed to functionalize nanoparticles for diverse biomedical applications.¹³⁰ For instance, Lu and her colleagues, working in myocardial ischemia-reperfusion injury (MIRI), engineered macrophage membrane nanoparticles overexpressing both hemagglutinin (HA) and the receptor for advanced glycation end products (RAGE), which enhanced endosomal escape and targeted infarct areas rich in S100A9 protein, thereby attenuating pro-inflammatory responses.¹⁸ Similarly, Jiang et al combined neutrophil membranes with HA and integrin ligands to create a nanosystem that specifically targets integrin-α9 in MIRI, improving siRNA delivery while minimizing degradation and off-target effects.¹⁰⁸ In neuroinflammatory contexts such as Alzheimer’s disease, hybrid nanoparticles composed of platelet membranes and chemokine receptor CCR2-overexpressing cell membranes demonstrated enhanced BBB penetration and targeted delivery to neuroinflammatory lesions by responding to upregulated CCL2 ligands. By sequestering CCL2, CCR2 overexpression achieves dual benefits, for it can improve targeting while decreasing macrophage infiltration, pro-inflammatory microglial polarization, and neuronal apoptosis.¹³¹ Furthermore, to achieve higher sensitivity for better targeting efficacy, Bu et al developed a HaloTag-anchored membrane receptor system for screening tyrosine kinase inhibitors, with a detection limit of 0.3 × 10⁻³ μg/mL.¹³² Due to their small dimensions, simple synthesis, and reduced immunogenicity, peptide-based targeting ligands like RVG29, T7, Angiopep-2, and mApoE have also been broadly adopted for targeting receptors on the BBB and brain cells.¹³³

Extracellular Vesicles (EVs)

EVs are nanoscale lipid bilayer-enclosed particles derived from various cell types, including cytotoxic T cells, platelets, neurons, and intestinal epithelial cells.¹³⁴ EVs mainly include microvesicles, exosomes, and apoptotic bodies, and they transport diverse cargoes such as proteins, lipids, and nucleic acids, with their molecular composition varied by subtype, cellular origin, and microenvironment.¹³⁵ For example, exosomes generally contain ESCRT proteins like Alix and TSG101, whereas microvesicles are abundant in glycoproteins and phosphoproteins.¹³⁶ Due to their natural homing capability, the biodistribution of EVs largely depends on their parent cell source. For instance, melanoma-derived EVs are mainly taken up by the lungs and spleen, while EVs derived from endothelial cells or platelets primarily target murine endothelium, allowing targeted drug delivery with minimized off-target effects.¹³⁷ In addition to serving as drug carriers, EVs are readily accessible sources of biomarkers, as seen in the use of small EVs from human peripheral blood carrying hERG1 and Hsp47 to non-invasively detect heart failure and cardiac ischemia.¹³⁸ EVs are also promising therapeutic targets. Platelet-derived EVs expose phosphatidylserine to promote coagulation, while under high phosphate conditions, vascular cells release EVs enriched with pro-calcific cargoes such as BMP-2 and Sortilin that drive vascular calcification, indicating that inhibiting EV release may be a therapeutic strategy.¹³⁹

Leveraging these advantages, researchers have explored EV-based therapies for CVD. Platelet-derived EVs transfer microRNA-34c-5p to endothelial cells, suppressing pro-inflammatory cytokines and reducing atherosclerotic lesions. Arslan et al further showed that mesenchymal stem cell-derived exosomes reduced myocardial infarct size by 45% by activating PI3K/Akt survival signaling via CD73 and adenosine receptors.¹⁴⁰ To enhance targeting performance, engineering strategies such as fusing a cardiac-targeting peptide with LAMP-2B on EV membranes or overexpressing CXCR4 have been shown to improve heart distribution and therapeutic efficacy.¹⁴¹

Despite these advantages, several intrinsic limitations hinder the clinical translation of EVs relative to biological membrane-coated synthetic nanoparticles. EVs have poor half-lives of only a few minutes, whereas synthetic nanoparticles can evade macrophage recognition and have longer circulation time. EV heterogeneity complicates isolation and purification, and drug loading procedures may further increase macrophage-mediated clearance.¹⁴² Scalable manufacturing is also a major challenge, for the production of EVs are mainly conducted by ultracentrifugation, which is not suited for large-scale production.

TCM Monomers in the Treatment of CVD

Atherosclerosis (AS)

Atherosclerosis (AS) is a progressive, multifaceted inflammatory disease that mainly targets large and medium-sized arteries. Its pathology involves the formation and gradual accumulation of atherosclerotic plaques, which feature a distinct structure composed of lipids, necrotic cores, calcified regions, and a mixture of cell types, including inflamed smooth muscle cells, endothelial cells, immune cells, and foam cells.²¹

Ginsenoside Rb1

The active constituents of Panax ginseng, ginsenosides, have been extensively explored for their diverse cardiovascular benefits, including improved circulation, antioxidant activity, vascular modulation, enhanced cardiac function, inhibition of platelet aggregation, and lipid profile regulation.¹⁴³ Of these, Ginsenoside Rb1, a natural tetracyclic triterpenoid saponin, exhibits notable anti-inflammatory, antioxidant, and anti-apoptotic effects. Damaged endothelial cells are the main components of atherosclerotic plaque. Through activation of the SIRT1/AMPK signaling pathway, Rb1 specifically mitigates endothelial senescence. This leads to reduced PAI-1 expression and upregulated eNOS, thereby enhancing NO production.¹⁴⁴ Additionally, to combat oxidative stress, a hallmark of AS, Ginsenoside Rb1 drives the nuclear translocation and activation of the transcription factor Nrf2. This is achieved through modulation of the Keap1-SYVN1 interaction and the formation of p47phox/Nrf2 complexes, thereby enhancing the antioxidant defense system.¹⁴⁵ Its anti-inflammatory actions are mediated by binding to the glucocorticoid receptor, which in turn modulates NF-κB and MAPK signaling pathways, effectively lowering the levels of pro-inflammatory cytokines.¹⁴⁶ Rb1 also stabilizes atherosclerotic plaques by polarizing macrophages to the anti-inflammatory M2 phenotype. This is accompanied by increased IL-4, IL-13, and STAT6 phosphorylation, alongside suppression of pro-inflammatory mediators IL-1β, IL-6, TNF-α, and facilitated lipid metabolism in foam cells.¹⁴⁷ Moreover, Rb1 induces autophagy, which is critical to its anti-apoptotic and atheroprotective actions.¹⁴⁸ However, despite these promising bioactivities, poor solubility, low oral and injectable bioavailability, and off-target effects can significantly impede the clinical translation of Rb1.

Colchicine

As the principal alkaloid of Colchicum autumnale, colchicine exerts potent anti-atherosclerotic activity largely via its anti-inflammatory and immunomodulatory properties. Mechanistically, it significantly suppresses the NLRP3 inflammasome, thereby reducing production of IL-1β and IL-18, key cytokines associated with plaque development and destabilization.¹⁴⁹ Beyond inflammasome inhibition, colchicine diminishes the formation of NETs, suppresses neutrophil chemotaxis, and inhibits superoxide production, thereby further reducing vascular inflammation.¹⁵⁰ It also directly influences platelet function by inhibiting cofilin and LIM domain kinase 1, reducing the release of β-thromboglobulin during platelet activation, and suppressing leukocyte-platelet aggregation.¹⁵¹ At the vascular level, colchicine also exerts multiple effects, for it reduces endothelial selectin expression, inhibits leukocyte activation and lytic enzyme release, stimulates anti-inflammatory cytokines such as IL-10 and TGF-β, and limits the proliferation of smooth muscle cells (SMCs) and fibroblasts, both of which can contribute to vascular thickening and calcification.¹⁵² Nevertheless, colchicine’s clinical utility is severely limited by a narrow therapeutic window and significant adverse effects. These include frequent gastrointestinal disturbances and increased susceptibility to infections. More seriously, it can cause various blood dyscrasias such as myelosuppression, leukopenia, and aplastic anemia.¹⁵³ This toxicity arises from its fundamental mechanism of binding to tubulin and disrupting microtubule networks, which impairs protein assembly, alters cellular morphology, and arrests mitosis, potentially leading to multi-organ dysfunction.¹⁵⁴

Artemisinin

Derived from Artemisia annua L., artemisinin is a natural sesquiterpene lactone that exhibits comprehensive anti-atherosclerotic activity through interconnected mechanisms targeting inflammation, oxidative stress, and foam cell formation. It attenuates vascular inflammation by reducing pro-inflammatory cytokines and chemokines in aortic tissues.¹⁵⁵ Concurrently, it suppresses oxidative damage by inhibiting malondialdehyde (MDA) and caspase 3/7 activity, while activating superoxide dismutase (SOD) and enhancing nitric oxide production via the PI3K/Akt/eNOS signaling pathway.¹⁵⁶ A crucial aspect of its action is the targeting of macrophage-derived foam cells, for artemisinin inhibits foam cell formation and induces macrophage autophagy via the AMPK/mTOR/ULK1 pathway, thereby attenuating plaque development.¹⁵⁷ The anti-inflammatory actions of artemisinin are further driven via diminished NF-κB phosphorylation and reduced NLRP3 inflammasome expression within macrophages.¹⁵⁸ It also interferes with early atherogenic events through suppression of ICAM-1 and VCAM-1 expression, which blocks monocyte-endothelial adhesion.¹⁵⁹ Regarding vascular remodeling, which is driven by VSMC proliferation, migration, and neointima formation, artemisinin can reduce PCNA, MMP-2, and MMP-9 expression and prevents VSMC phenotype switching, thereby targeting these key processes.¹⁶⁰ Although artemisinin has a favorable clinical safety profile, high doses in animal studies have shown potential neurotoxicity, possibly mediated through oxidative stress and heme-potentiated toxicity mechanisms.¹⁶¹

Proanthocyanidin

Complementing artemisinin’s effects, proanthocyanidin, a widespread polyphenol found in numerous edible plants, demonstrates equally multifaceted anti-atherosclerotic properties. A fundamental mechanism is its ability to prevent LDL oxidation, a critical initiating event in AS, thereby protecting endothelial cells and impeding foam cell formation.¹⁶² By decreasing LOX-1 and L-selectin levels, proanthocyanidin disrupts the CRP-ox-LDL interaction and enhances endothelial NO production, which therefore inhibits endothelial cell apoptosis, proliferation, and migration.¹⁶³ Furthermore, these effects can be augmented by reducing adhesion molecules such as P-selectin and ICAM-1, as well as by specifically interfering with TNF-α-induced VCAM-1 and MCP-1 expression.¹⁶⁴ Pharmacokinetic studies have also indicated favorable absorption and metabolism for proanthocyanidins without significant toxicity, supporting their cardioprotective and antioxidant potential.¹⁶⁵

Berberine

Berberine, an isoquinoline alkaloid derived from Coptis chinensis and Berberis vulgaris, exhibits broad-spectrum anti-atherosclerotic activity via multiple pharmacological mechanisms, including endothelial protection, inflammation, metabolism, and cellular homeostasis.¹⁶⁶ Berberine directly shields endothelial cells from oxidative injury by promoting Nrf2 nuclear translocation to upregulate HO-1.¹⁶⁷ This antioxidative effect is amplified in macrophages, where berberine suppresses the NLRP3 inflammasome to inhibit NF-κB signaling and IL-1β release, while activating AMPK to reduce ROS accumulation. Systemically, it modulates gut microbiota by inhibiting bacterial enzymes CutC and FMO to reduce pro-atherogenic TMAO production and increase anti-inflammatory SCFA concentrations.¹⁶⁸ Metabolically, berberine corrects dyslipidemia by targeting regulators like LDLR, AMPK, and PCSK9 to reduce intestinal cholesterol absorption and promote hepatic cholesterol turnover.¹⁶⁹ It further enhances fatty acid oxidation and activates macrophage autophagy via SIRT1-mediated TFEB nuclear translocation to protect plaque cells from stress and apoptosis.¹⁷⁰ In foam cells, berberine reduces lipid synthesis (via FASN, SREBP1) while enhancing cholesterol efflux (via ABCA1, ABCG1) through AMPKα activation.¹⁷¹ Its anti-inflammatory reach is broad, for it can not only reduce serum adhesion molecules (ICAM-1, VCAM-1) and M1-type cytokines, but also alleviates SASP-related inflammation in aging foam cells by activating PPARγ and promoting GATA4 ubiquitination.¹⁷² Despite its comprehensive profile, berberine’s clinical translation faces severe constraints due to poor oral bioavailability (<1%), which stems from low intestinal permeability, extensive first-pass metabolism, and poor aqueous solubility.¹⁷³

Thrombus

Thrombosis, defined as the formation of thrombi composed of fibrin, platelets, red blood cells, leukocytes, and neutrophil extracellular traps, represents a major complication of CVD that can precipitate MI, IS, and venous thromboembolism.¹⁷⁴ The core mechanisms of thrombus formation begin with platelet aggregation and coagulation cascade activation. Following vascular injury, exposed subendothelial collagen promotes platelet adhesion via integrin αIIbβ3, triggering activation and release of ADP and thromboxane A2. The interaction between vWF and the platelet glycoprotein Ibα-V-IX complex amplifies this process, promoting the recruitment of further platelets and facilitating the formation of a hemostatic plug.¹⁷⁵

Lumbrokinase

Lumbrokinase, a purified enzyme complex derived from earthworms, exerts its thrombolytic effect through two primary mechanisms, namely the direct fibrin degradation and the generation of active plasmin from plasminogen via upregulation of endogenous tissue-type plasminogen activator (t-PA) activity, which collectively diminishes blood viscosity and suppresses platelet aggregation.¹⁷⁶ In addition to fibrinolysis, it also demonstrates anticoagulant effects via platelet inhibition, leading to prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT).¹⁷⁷ It also enhances vascular endothelial growth factor (VEGF) production and endothelial cell migration, alongside anti-inflammatory effects mediated by decreased IL-6 and TNF-α levels in macrophages¹⁷⁸ Furthermore, lumbrokinase modulates cellular stress responses by downregulating NF-κB and upregulating manganese-dependent superoxide dismutase, thereby enhancing autophagic flux and mitigating oxidative damage and apoptosis.¹⁷⁹ A key advantage over traditional thrombolytics like urokinase and streptokinase is its superior safety profile. Due to its high specificity for fibrin and its mechanism that avoids uncontrolled plasminogen activation, lumbrokinase does not cause severe or life-threatening bleeding.¹⁸⁰ Nevertheless, short circulation half-life, rapid enzymatic degradation, and potential hemolytic effects still remain to be the significant barriers to its clinical application.¹⁸¹

Hirudin

Composed of 64–66 amino acids and possessing a molecular weight of around 7000 Da, hirudin is a polypeptide derived from the salivary glands of Hirudo medicinalis.¹⁸² It extends thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (APTT) through tight and nearly irreversible binding to thrombin, which is mediated by ionic bonds and hydrophobic forces, thereby blocking thrombin-mediated fibrinogen cleavage and subsequent fibrin formation.¹⁸³ Unlike traditional anticoagulants such as heparin, hirudin offers a key advantage, for it is not bound or inactivated by platelet factors, and its small molecular size enables it to reach and inhibit thrombus-bound thrombin, which is inaccessible to heparin–antithrombin complexes.¹⁸⁴ In addition to its anticoagulant properties, hirudin also promotes vascular endothelial function via the alleviation of oxidative stress injury and inflammatory responses, dose-dependent regulation of MMP-9, VCAM-1, p-ERK1/2/ERK1/2, and p-P65/P65 expression, and inhibition of apoptosis.¹⁸⁵ Despite these therapeutic benefits, the clinical application of recombinant hirudin is hampered by a variety of factors, including the need for intravenous administration, poor serum stability, susceptibility to protease degradation, rapid clearance, and a short half-life of approximately 60–100 minutes. These limitations mentioned above can collectively lead to its low bioavailability. Furthermore, its clinical application is constrained by an increased risk of unexpected bleeding.¹⁸⁶

Ginsenoside Rg1

Ginsenoside Rg1, a 20(S)-protopanaxatriol-type saponin derived from ginseng roots or stems, is recognized for its particularly high biological activity.¹⁸⁷ Given that thrombin-mediated platelet activation is central to thrombosis, Rg1 represents a promising candidate for novel antithrombotic therapies. The mechanism behind which is that it modulates the platelet PKC–MAPK pathway, leading to downregulation of ERK phosphorylation and P-selectin expression, thereby suppressing platelet aggregation and adhesion, while also reducing thrombin–fibrinogen binding.¹⁸⁸ In addition to its antiplatelet activity, Rg1 alleviates inflammation through inhibition of the NF-κB and TLR4/NF-κB/NLRP3 pathways, activation of the AMPK/Nrf2/HO-1 axis, and regulation of macrophage polarization, all of which collectively contribute to attenuating thrombus formation.¹⁸⁹ However, despite these promising properties, the oral application of Rg1 is limited by its instability in gastric environments and poor intestinal mucosal permeability.¹⁹⁰

Myocardial Infarction (MI)

Myocardial infarction (MI) typically results from atherosclerotic plaque rupture followed by thrombotic coronary artery occlusion, severely restricting myocardial blood supply.¹⁹¹ Though revascularization achieved through percutaneous coronary intervention or coronary artery bypass grafting is indispensable for reestablishing perfusion, the subsequent reperfusion phase can paradoxically amplify tissue damage, a process defined as myocardial ischemia-reperfusion injury (MIRI). This complex pathophysiology involves oxidative stress, inflammatory activation, calcium dysregulation, and programmed cell death pathways, collectively driving cardiomyocyte loss and adverse ventricular remodeling.

Berberine

Berberine’s therapeutic efficacy in MI is mediated by a complex mechanism that involves regulating inflammation, apoptosis, oxidative stress, fibrosis, and autophagy. Through suppression of the PI3K/Akt signaling pathway, it primarily modulates the inflammatory response, which reduces the release of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α in myocardial tissue.¹⁹² Simultaneously, within the infarcted heart, berberine induces monocyte polarization to M2 macrophages, thereby cultivating an immune environment conducive to tissue repair.¹⁹³ In addition to inflammation, berberine can reduce oxidative stress in multiple ways. It suppresses cardiomyocyte apoptosis through downregulation of Apaf-1, caspase-3, and caspase-9 via the PI3K/AKT pathway.¹⁹⁴ It also counteracts mitochondrial dysfunction in MIRI through improved complex I activity and elevated cytochrome c levels within mitochondria.¹⁹⁵ Additionally, it alleviates endoplasmic reticulum stress via activation of SIRT1 signaling and downregulation of PERK and eIF2α phosphorylation.¹⁹⁶ Its antioxidant properties are reflected in reduced myocardial superoxide generation and malondialdehyde levels, alongside increased superoxide dismutase activity.¹⁹⁷ With respect to fibrotic remodeling, berberine suppresses the transformation of cardiac fibroblasts into myofibroblasts and diminishes extracellular matrix protein(ECM) accumulation, thereby attenuating myocardial fibrosis and adverse ventricular remodeling.¹⁹⁸ It further suppresses apoptosis in heart failure by modulating the CHOP/caspase-12 pathway and upregulating the Bcl-2/Bax ratio, while facilitating autophagy and alleviating left ventricular remodeling by suppressing p38 MAPK and activating phospho-Akt signaling.¹⁹⁹ Together, these coordinated mechanisms lead to enhanced hemodynamic function, including increased left ventricular ejection fraction and fractional shortening, along with diminished infarct size. In spite of these promising therapeutic effects, the inadequate oral bioavailability of berberine (<1%), resulting from inadequate intestinal absorption, low molecular permeability, extensive intestinal and hepatic first-pass metabolism, and poor aqueous solubility, has substantially hampered its clinical use.¹⁷³

Resveratrol

Extracted from grapes and red wine, resveratrol (3,4,5-trihydroxystilbene) is a natural polyphenolic antioxidant which can protect against MI via a multifaceted mechanism involving the modulation of autophagy, anti-inflammatory effects, alleviation of oxidative stress, suppression of ferroptosis, and enhancement of angiogenesis. Its robust anti-inflammatory activity is manifested by the downregulation of IL-2 and IFN-γ derived from lymphocytes, coupled with the suppression of macrophage-derived TNF-α and IL-12, which can therefore promote post-infarction cardiac healing and reverse left ventricular remodeling.²⁰⁰ By exerting potent free radical scavenging activity, resveratrol confers cardioprotection through specific inhibition of mitochondrial ferroptosis and upregulation of SIRT1, GPX4, and FTH-1 protein expression.²⁰¹ Beyond reducing infarct size and apoptosis, resveratrol improves coronary flow and left ventricular pressure, counteracts cardiac fibrosis by downregulating collagen I, collagen III, TGF-β, and α-SMA expression, and protects endothelial cells by increasing VEGF-B, p-eNOS, and p-AMPK expression alongside NO production.²⁰² Moreover, it promotes angiogenesis through upregulation of eNOS, iNOS, VEGF, and Flk-1 in ischemic heart tissue, along with activating endogenous Sca-1⁺ cardiac stem cells to boost capillary density.²⁰³ These integrated mechanisms contribute to the improvement of cardiac function and the reduction of infarct size post-MI. Nevertheless, despite its multifaceted advantages, resveratrol’s clinical translation is severely limited by its poor aqueous solubility, inadequate absorption, limited membrane transport, and consequently low bioavailability.²⁰⁴

Allicin

Allicin, the principal bioactive compound derived from garlic, exerts its cardioprotective effects in MI and MIRI through a coordinated network of redox, inflammatory, calcium-regulatory, and pro-angiogenic mechanisms. Its protective actions are primarily mediated through redox-dependent interactions with thiol groups, which form the basis for its modulation of multiple pathological pathways.²⁰⁵ In MIRI, inflammatory response and calcium overload are the primary pathogenic factors. Allicin mitigates NLRP3 inflammasome activation triggered by Ca²⁺ influx and ROS accumulation, achieved through upregulation of the inflammasome inhibitor SHP2 and downregulation of p-PERK, MFN1, and NOX proteins.²⁰⁶ As for calcium loading, allicin maintains calcium homeostasis by promoting hydrogen sulfide production, which modulates calcium channels and sarcoplasmic reticulum calcium release, thereby improving cardiomyocyte contractility.²⁰⁷ It further enhances SERCA-dependent calcium reuptake and NCX-dependent calcium removal while reducing expression of calcium-handling proteins such as p-CaMKII and p-RyR2.²⁰⁸ Allicin also reverses calcium overload-induced apoptosis through the inhibition of the PI3K-mediated GRK2/PLC-γ/IP3R pathway. This is evidenced by decreased pro-apoptotic markers, including Bax, cleaved caspase-3, and cytosolic cytochrome c, and increased anti-apoptotic Bcl-2, thereby resulting in dose-dependent decreases in the release of cardiac enzyme.²⁰⁹ Furthermore, by activating the PI3K/AKT/mTOR pathway and upregulating the expression of Cox-2 and VEGF, allicin alleviates cardiac fibrosis and enhances capillary angiogenesis within the peri-infarct zone.²¹⁰ The vascular repair capacity of allicin is further augmented by its degradation byproducts, diallyl polysulfides, which act as hydrogen sulfide (H₂S) donors. These molecules potentiate endothelial nitric oxide synthase (eNOS) activity and increase nitric oxide (NO) bioavailability, consequently inducing vasorelaxation.²¹¹ In MI models, allicin’s therapeutic effects are linked to modulation of the JNK signaling pathway and beneficial remodeling of gut microbiota, characterized by increased protective bacteria such as Lactobacillus and reduced harmful Parasutterella, changes that correlate with improved cardiac function and decreased inflammatory cytokines.²¹² Collectively, these integrated mechanisms enable allicin to preserve cardiac function, reduce infarct size, and limit adverse remodeling following myocardial injury. However, some studies have revealed that free allicin can get trapped when it reacts with the fatty acids and proteins located on the plasma membrane, thereby restraining its therapeutic efficacy. Furthermore, systemic administration of allicin is primarily hindered by poor target specificity and the risk of off-target toxicity.²¹³

Puerarin

Puerarin (daidzein-8-C-glucoside) is an isoflavone glycoside from Radix Puerariae that can confer broad-spectrum cardioprotection against MI via multiple mechanisms, including anti-inflammation, antioxidation, and the regulation of multiple pathways.²¹⁴ During MIRI, it alleviates oxidative stress by reducing serum levels of MDA and CK while increasing SOD activity.²¹⁵ Puerarin mitigates ER stress and downstream mitochondrial dysfunction by activating the KLF4/Mzb1 axis, which can thereby downregulate ER stress markers, including GRP78 and CHOP.²¹⁶ Puerarin also exerts anti-inflammatory effects by polarizing recruited monocytes/macrophages to the reparative M2 phenotype. This action helps maintain connexin 43 (Cx43) expression, which helps to enhance intercellular coupling and electrical conduction in the heart.²¹⁷ When combined with tanshinone IIA, puerarin inhibits M1 macrophage expression during the early inflammatory stage while increasing M2 macrophage expression, and the mechanism behind which can be associated with the inhibition of toll-like receptor 4 (TLR4) signaling.²¹⁸ When it comes to tissue remodeling, it attenuates post-MI cardiac fibrosis via the suppression of F4/80, MCP-1, and TGF-β1 expression within cardiac tissue.²¹⁹ Regarding cell death regulation, puerarin counters ferroptosis, which is a critical process in MI pathogenesis, by decreasing ROS while increasing glutathione and ATP levels. It further attenuates pathological autophagy during reperfusion through the upregulation of HES1 and p62 protein expression, coupled with the suppression of the LC3II/I ratio.²²⁰ Furthermore, puerarin mitigates MI by upregulating angiogenic factors, including VEGFA, Ang-1, and Ang-2, to reduce ventricular dilation, and by enhancing NO/eNOS expression to facilitate coronary microvascular recanalization.²²¹ Notwithstanding these favorable effects, its clinical utility remains restricted due to inadequate solubility and poor bioavailability.²²²

Ischemic Stroke (IS)

Ischemic stroke (IS) is a serious neurological condition caused by blocked blood vessels in the brain, mainly due to AS, cardiogenic embolism, and small vessel occlusion. After blood flow is disrupted, ischemic brain damage progresses through two stages. First, a core of irreversibly damaged necrotic tissue forms within the affected vascular bed. Subsequently, late-phase injury develops in the peri-infarct area, a potentially salvageable zone surrounding the core.²²³ While recanalization remains the only approved treatment, its efficacy is constrained to a narrow therapeutic window of under 4.5 hours.²²⁴

Baicalin

Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exerts comprehensive neuroprotection in IS.²²⁵ It maintains mitochondrial integrity during cerebral ischemia-reperfusion via the suppression of the fission mediator Drp-1, the augmentation of the fusion regulator MFN2, and the AMPK pathway activation, thereby preserving mitochondrial membrane potential.²²⁶ Building on this foundation, baicalin modulates astrocyte responses in a balanced manner, for it enhances neuronal survival by upregulating BDNF release and activates the BDNF-TrkB pathway, while also mitigating neuroinflammation via suppression of astrocyte activation and the reduction of IL-6, IL-1β, and TNF-α secretion.²²⁷ Extending its anti-inflammatory effects to microglia, baicalin regulates the SIRT1/HMGB1 pathway and suppresses the miR-181b/HMGB1/TLR4/NF-κB axis via CD14 inhibition, thereby reducing production of TNF-α, IL-1β, and other inflammatory mediators.²²⁸ Beyond inflammation control, baicalin directly counteracts multiple cell death pathways, for it inhibits ferroptosis by increasing GPX4, FTH1, and SLC7A11 while decreasing ACSL4 and total iron levels, mediates anti-apoptotic activity by upregulating the Bcl-2/Bax ratio, and protects against excitotoxicity.²²⁹ It further addresses post-stroke metabolic dysfunction by attenuating succinate dehydrogenase-mediated ROS overproduction and restoring ATP production via LonP1 and HIF-1α signaling regulation. Additional protection comes from upregulating TREM2 receptors on microglia to reduce oxidative stress.²³⁰ Notwithstanding its multifaceted neuroprotective properties and BBB penetration capability, the clinical application of baicalin is severely constrained by inadequate intestinal permeability and poor oral bioavailability of approximately 2.2% due to required hydrolysis by gut microbiota.²³¹

Paeonol

Paeonol, a phenolic compound derived from Paeonia suffruticosa, exerts comprehensive neuroprotection in IS through a multi-target mechanism. Its protective effects begin at the onset of MIRI, where it directly combats oxidative stress by suppressing and scavenging superoxide anions, while simultaneously curtailing microglial activation, as demonstrated by diminished populations of ED1- and IL-1β-immunoreactive cells within the cerebral infarct zone.²³² Building on this antioxidant foundation, paeonol significantly modulates the inflammatory cascade by interfering with toll-like receptor signaling pathways, particularly TLR2 and TLR4, which normally activate NF-κB through MyD88-dependent mechanisms to drive pro-inflammatory cytokine production.²³³ Therefore, by inhibiting the accumulation of TLR2-, TLR4-, and IL-1β-positive cells at infarct sites, paeonol effectively reduces cerebral infarction volume and improves neurological scores while decreasing TUNEL-positive cells, demonstrating substantial anti-apoptotic effects that are further supported by its direct suppression of cytosolic AIF accumulation and mitochondrial Bax protein expression.²³⁴ Extending beyond acute neuroprotection, paeonol addresses the later phases of IS pathology by mitigating reactive astrogliosis and glial scar formation, evidenced by reduced GFAP-positive astrocyte density and decreased Iba-1-positive microglial proliferation in both ischemic core and boundary regions.²³⁵ These protective effects are potentiated via pAkt/Nrf2/HO-1 pathway activation, which augments the cellular defense against oxidative stress through induction of Phase II detoxifying enzymes, while concurrently upholding BBB integrity by sustaining tight junction function.²³⁶ However, most anti-stroke agents have to tackle the problem of BBB, and poor drug delivery to ischemic lesions resulting from the BBB can significantly impair the therapeutic potential of these agents.²³⁷

Curcumin

Curcumin, a polyphenolic compound derived from Zingiberaceae plants, confers neuroprotection in IS by virtue of its anti-inflammatory, antioxidant, and anti-apoptotic properties.²³⁸ Mechanistically, it can inhibit the NLRP3 inflammasome by blocking DAMP-mediated ASC/pro-caspase-1 assembly. As a result, curcumin decreases the population of GSDMD⁺ and caspase-1⁺ microglia/macrophages and suppresses pyroptosis-related proteins such as GSDMD-N, cleaved caspase-1, NLRP3, IL-1β, and IL-18 by inhibiting the NF-κB pathway.^239,240 Curcumin also has anti-inflammation effect, for it can promote microglial M2 polarization via miR-205-5p/KLF2/ATF2 and miRNA-423-5p/NOD2 axes.²⁴¹ Network pharmacology further reveals involvement of multiple targets (NFKB1, TP53, AKT1, STAT3, TNF) and pathways (AGE-RAGE, Th17 differentiation, p53, necroptosis).²⁴² In addition to these molecular actions, curcumin sustains BBB integrity via upregulation of the tight junction constituents ZO-1, occludin, and claudin-5, while concurrently mitigating hippocampal neuronal atrophy and augmenting dendritic complexity.²⁴³ Regarding cell death regulation, curcumin attenuates ferroptosis by activating melatonin receptor 2/cAMP/PKA/IRE1 signaling to counteract iron accumulation, while also mediates anti-apoptotic activity by elevating Bcl-2, suppressing p53/Bax, and attenuating the expression of cleaved caspase-1, −3, and −4.²⁴⁴ At the subcellular level, it boosts mitochondrial function by stabilizing membrane potential, promoting complex I activity, raising cytochrome c levels, and improving biogenesis through higher NRF-1 and TFAM levels.²⁴⁵ Moreover, curcumin reverses calcium overload, which is also an important factor in IS progression, through downregulation of cleaved caspase-3 alongside upregulation of p-PKC-θ and Orai1.²⁴⁶ Despite these promising therapeutic effects and favorable safety profile, clinical translation is significantly hindered by suboptimal oral bioavailability (<1%), which is a consequence of rapid metabolism and systemic elimination.²⁴⁷

The Impact of Cell Membrane Nanotechnology on the Therapeutic Effects of TCM Monomers

Atherosclerosis (AS)

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid deposition and leukocyte infiltration within the arterial wall, during which macrophages possess an inherent “homing” capacity to atherosclerotic lesions. This pathological tropism primarily stems from integrin α4β1 on the macrophage surface, which actively binds to VCAM-1, a molecule highly expressed on the inflamed endothelium of atherosclerotic plaques. Exploiting this natural tropism, researchers have developed biomimetic nanotherapies for targeted drug delivery. As an example, rapamycin-loaded nanoparticles coated with macrophage or leukocyte membranes exhibit improved accumulation in the aortic arch and plaque regions, while significantly minimizing off-target deposition in the liver and kidneys. These membrane-coated systems also provide a controlled drug release profile and improved safety, as demonstrated by reduced lung interstitial thickness and lower LDH levels compared to free rapamycin, mitigating the adverse effects associated with systemic rapamycin administration.¹⁹

Beyond targeted delivery, a core therapeutic goal is addressing the dysfunctional lipid metabolism in foam cells, which are central to plaque initiation and progression. During the early stages of AS, foam cells play a role in generating the lipid-rich core and fibrous cap of plaques. In contrast, during the late stage of lesion development, large numbers of necrotic and apoptotic foam cells gather into the necrotic core, which aggravates inflammation and leads to plaque destabilization.²⁴⁸ To this end, Li et al have used cell membrane-coated nanoparticles to encapsulate methotrexate, and found that these nanoparticles suppress foam cell formation by reducing oxLDL uptake while increasing its efflux.²⁴⁹ Another sophisticated strategy involves plaque/macrophage dual-targeting nanoparticles that synchronously regulate lipid metabolism by activating autophagy and downregulating CD36, while also promoting the repolarization of macrophages from the pro-inflammatory M1 phenotype to the reparative M2 phenotype.¹²⁸

Inflammation, alongside traditional risk factors, has emerged as a fundamental player in atherosclerotic plaque development. Macrophage membrane coatings exert anti-inflammatory effects by inhibiting pro-inflammatory cytokines such as TNF-α and IFN-γ while promoting IL-10. The therapeutic potential is further reinforced by platelet membrane-coated curcumin nanoparticles, which decrease IL-6 secretion and downregulate NF-κB and TGFB1 expression, reflecting robust anti-inflammatory and antifibrotic effects.²⁵⁰ Further enhancing therapeutic efficacy, these nanoplatforms can also mitigate key cellular stressors and improve drug penetration. Overproduction of ROS are closely involved in the progression of AS, and platelet membrane coatings have been shown to significantly reduce intracellular ROS levels and attenuate endoplasmic reticulum(ER) stress via decreased transcription of genes involved, namely CHOP, GRP78, and eIF2α.²⁵¹ In parallel, the promotion of autophagy is a process known to inhibit AS progression.²⁵² Using erythrocyte membrane-coated nanoparticles loaded with Astragaloside IV, Ding’s group has demonstrated that these nanoparticles enhanced autophagy activation, as evidenced by increased levels of the LC3II marker.²⁵³ Moreover, to overcome the challenge of drug leakage and poor retention, advanced designs like platelet membrane-coated porous nanomotors have been introduced. Capable of deep penetration into plaques, these autonomous systems can enhance drug retention, enabling a combined approach that delivers short-term photothermal ablation of inflammatory macrophages alongside long-term anti-proliferation.²⁵⁴

Optimizing this multi-targeted approach, Yin et al engineered a biomimetic selenium/ginsenoside Rb1 nanocarrier system (PM@Se/Rb1 NPs) that enhances biocompatibility and facilitates active plaque targeting, demonstrating the capacity to suppress ICAM-1 expression and inhibit abnormal angiogenesis in vitro, while significantly lowering plaque burden in the aortic arches and roots in vivo. Furthermore, these nanoparticles drastically improved systemic lipid profiles by decreasing circulating LDL-c, TG, and TC while increasing HDL-c, collectively establishing a highly efficient therapeutic strategy for comprehensive AS management.²⁵⁵ To maximize therapeutic efficacy while overcoming traditional systemic limitations, a parallel biomimetic nanoplatform utilizing macrophage membrane-coated colchicine nanoparticles was developed, wherein the preserved CD47 membrane protein significantly inhibits macrophage phagocytosis to extend circulation while enhancing cellular uptake by activated endothelial cells within the lesions. In vivo evaluations of this system reveal superior performance in plaque regression and stabilization, mediated primarily through marked collagen deposition, thus offering a promising targeted strategy for AS therapy.²⁵⁶ This emphasis on structural remodeling is echoed by an innovative erythrocyte-coated nanocomplex system co-delivering artemisinin and proanthocyanidins, which leverages biomimetic immune evasion to extend blood circulation time and achieve specific plaque targeting, ultimately confirming via in vivo evaluations that these nanoparticles effectively inhibit necrotic core expansion and increase plaque collagen content.²⁵⁷

Furthermore, to bridge the gap between inflammation resolution and endothelial repair, M2 macrophage membrane-coated berberine nanoparticles have been engineered to exhibit improved plaque targeting while minimizing off-tissue deposition in major organs. These specific nanoformulations significantly reduce aortic plaque area, lipid deposition, and necrotic core formation while increasing collagen content and plaque stability; this structural repair is accompanied by a dramatic reduction in pro-inflammatory cytokines, an increase in anti-inflammatory mediators within the aortic lesions, the direct repolarization of M1 macrophages to the protective M2 phenotype, and augmented endothelial repair mediated by increased CD31 and VEGF expression, thereby successfully optimizing berberine’s therapeutic performance in AS treatment.¹⁶²

Thrombus

The clinical utility of the conventional thrombolytic agents is still hampered by a lack of active targeting capability, thus leading to high bleeding risks. Therefore, researchers have turned to the application of external energy sources, which have significantly advanced targeted therapeutic strategies. Ultrasound-mediated drug delivery systems leverage the phase-transition capabilities of perfluorocarbons, where ultrasound-triggered conversion of perfluorohexane(PFH) to microbubbles enables controlled drug release from liposomal carriers. Based on this principle, Xu et al engineered RGD-modified red blood cell membrane-coated PLGA nanoparticles co-encapsulating urokinase and perfluoropentane, demonstrating that ultrasound triggering achieved approximately 60% drug release within 5 minutes, which is three fold higher than non-membrane-coated counterparts. The RBC membrane coating concurrently provided effective immune evasion, significantly reducing macrophage phagocytosis compared to uncoated nanoparticles.¹²

Complementing ultrasound approaches, thermal-based strategies have demonstrated remarkable efficacy in thrombolysis enhancement, as localized hyperthermia facilitates thrombus penetration by loosening non-covalent fibrin interactions and promoting nanoparticle infiltration. Utilizing these, Zhu et al engineered a magnetic hyperthermia thrombolysis system incorporating platelet membrane-coated nanoparticles that achieved exceptional thrombolytic rates of 82.4% under photothermal stimulation and 74.2% under magnetothermal stimulation, significantly surpassing the 15% efficacy of conventional urokinase. Notably, this system enabled substantial thrombolysis, for it dramatically reduced tPA concentrations (from 10 mg/kg to 0.13 mg/kg) while achieving 91.2% thrombus resolution within 5 days.²⁵⁸ ROS also contributes significantly to thrombus progression, for it can promote platelet-endothelium interactions, endothelial dysfunction, and vascular occlusion. To address this pathological mechanism, Zhao et al developed hydrogen peroxide-responsive nanoparticles camouflaged with platelet membranes that exhibited four fold higher accumulation in injured carotid arteries compared to non-camouflaged nanoparticles. This enhanced targeting was mediated by specific interactions between platelet membrane glycoproteins (GPIbα and GPVI) and thrombogenic substrates including vWF and collagen, while simultaneously demonstrating potent H₂O₂-scavenging capability through concentration-dependent reduction of intracellular ROS levels.²⁵⁹

Cell membrane selection also plays a pivotal role in this process, as membrane coating confers distinct thrombus-targeting properties to identical drug cores. Chen et al systematically compared RBC membrane and platelet membrane coating for fullerenol delivery, revealing that RBC membrane provided superior overall thrombus targeting with 38% and 61% enhancements in fibrin and clot adhesion respectively, alongside a 3.1-fold extended circulation time and a 69% reduction in macrophage phagocytosis, which ultimately translated to a 151% higher thrombus accumulation for RBC-coated nanoparticles compared to 57% for platelet-coated nanoparticles.²⁶⁰

Despite these advancements, conventional thrombolytic therapy still faces a persistent clinical challenge, namely the high risk of systemic bleeding due to non-specific coagulation factor consumption. To overcome this obstacle, Xu et al addressed this by developing platelet membrane-cloaked nanoparticles conjugated with rt-PA. While free rt-PA led to significant alterations, these nanoparticles preserved normal coagulation parameters (aPTT, FIB, PT, TT, and bleeding time), demonstrating that the biomimetic coating effectively restricts thrombolytic activity and reduces hemorrhagic complications.²⁶¹ Similarly, an innovative biomimetic nanoplatform has been developed, which encapsulates lumbrokinase within a PLGA core and envelops it with a platelet membrane. This design achieves three key outcomes, which are enhanced affinity for fibrin-rich thrombi and platelet aggregates, activation of platelets and endothelial cells in vitro, and a significant reduction in carotid thrombus area in vivo. By effectively decreasing the outer diameter (OD) value, this novel strategy demonstrates excellent targeting and thrombolytic capability at the thrombus site while simultaneously minimizing bleeding risks and cellular toxicity.²⁶²

The extensive application of this approach is further demonstrated by a dedicated platelet membrane-coated nanosystem constructed to exhibit enhanced binding to thrombin-induced plasma and fibrin clots in vitro, greater adhesion and aggregation at thrombotic sites, and improved hepatic evasion in vivo, a cascade likely mediated by the regulation of neutrophil activation wherein P-selectin expressed on the platelet membrane serves a vital homing function.²⁶³ To synthesize the benefits of multiple cell types, a hybrid biomimetic nanoplatform integrating both platelet and erythrocyte membranes was engineered, which markedly increased the drug loading and encapsulation efficiency of both the monomer ginsenoside Rg1 and perfluorohexane. This multi-membrane system demonstrated superior anticoagulant activity in vitro and achieved a clot inhibition rate of 88.20% alongside a thrombolytic efficacy of 30.96% in vivo, underscores its unique potential in comprehensive thrombus management.²⁶⁴

Myocardial Infarction (MI)

During MI, the inflammatory cascade is particularly critical, with neutrophils being the first responders to infiltrate infarcted myocardium. This natural homing mechanism has been leveraged for therapeutic targeting, as neutrophil membrane-coated nanoparticles demonstrate inflammatory chemotactic capability while prolonging circulation time and reducing hepatic clearance.²⁶⁵ Chen et al further confirmed that such nanoparticles specifically accumulate in peri-infarct macrophages and cardiomyocytes via LFA-1 and Mac-1 receptor interactions.⁵² The inflammatory damage-associated molecular pattern S100A8/A9 can also exacerbate tissue damage by recruiting innate immune cells, and Lu et al reported that siRNA nanoparticles coated with macrophage membranes effectively reduced myocardial cell death, reduced lactate dehydrogenase and cardiac troponin I release, and significantly diminished infarct size and fibrosis.¹⁸

Beyond immediate revascularization, comprehensive MI management requires addressing multiple injury phases and cellular processes. Thrombolysis remains first-line treatment for acute MI, and Guo et al fabricated platelet membrane-coated nanoparticles capable of co-delivering protocatechualdehyde and tissue plasminogen activator. By responding to the acidic ischemic microenvironment, these nanoparticles accomplish concurrent thrombolysis and ROS scavenging, thereby limiting mitochondrial damage.²⁶⁶ This mitigation of oxidative stress is particularly significant in the pathology of MI, as NADPH oxidase 2 (Nox-2)-mediated superoxide production dramatically increases in infarcted myocardium, primarily driven by infiltrating macrophages, where the resulting ROS overproduction impairs mitochondrial function and induces cardiomyocyte apoptosis. To target multiple therapeutic windows simultaneously, Xu et al designed platelet membrane-coated nanocarriers that initially target MI/R lesions during ischemia-reperfusion phase, then subsequently recruit to inflammatory monocytes during late reperfusion, ultimately promoting STAT3 phosphorylation and inflammatory reprogramming.²⁶⁷

Concurrently, ferroptosis has emerged as another crucial cell death mechanism in MI pathology, characterized by iron overload and glutathione peroxidase 4 (GPX4) downregulation. To address this, Song et al developed platelet membrane-coated nanoparticles co-loaded with the ferroptosis inhibitor Ferrostatin-1 and an anti-CD47 antibody, which collectively reduced lipid ROS by nearly 40% while restoring SLC7A11, GPX4, and glutathione levels, significantly mitigating post-MI ferroptosis and inflammation.²⁶⁸ To further enhance targeting specificity to inflamed myocardium, Wang et al developed hybrid membrane coatings from mesenchymal stem cells and macrophages, finding that miR-125b surface modification reduced macrophage uptake while macrophage membrane components improved nanoparticle escape capability.²⁶⁹

Aging is also a significant factor in the progression of MI, driving nearly 50% of patients towards adverse remodeling including cardiomyocyte hypertrophy, fibrosis, and heart failure. Gu et al identified p16 as promoting STAT3-dependent NLRP3 transcription in aging fibroblasts, exacerbating post-MI pathological remodeling, and consequently developed neutrophil membrane-artificial lipid hybrid nanoparticles specifically targeting cardiac fibroblasts.²⁷⁰

To translate these drug delivery nanosystems into optimized clinical candidates, biomimetic membrane coating has been increasingly integrated with TCM monomers to overcome their intrinsic bioavailability limitations and unlock their multi-target potentials. For instance, nanoparticles coated with platelet membrane have been engineered, exhibiting improved targeting to the infarcted myocardium while reducing hepatic uptake. These nanoformulations yield significant improvements in ejection fraction and fractional shortening, downregulation of left ventricular internal dimensions (LVIDd, LVIDs), end-systolic volume, end-diastolic volume, and cardiac collagen deposition, decreased collagen I/III ratio and myocardial stiffness, enhanced angiogenesis, reduced cardiomyocyte apoptosis and TNF-α levels, and increased reparative M2 macrophages alongside decreased inflammatory M1 macrophages, which collectively demonstrate the substantial potential of biomimetic coating strategies for optimizing berberine’s therapeutic performance in MI treatment.²⁷¹ In parallel with this protective efficacy against adverse remodeling, macrophage membrane-coated nanoparticles have been developed to address these challenges, exhibiting improved targeting to injured myocardium while minimizing off-target deposition. These nanoformulations substantially enhance ejection fraction and fractional shortening while attenuating left ventricular internal dimensions, end-systolic volume, infarct size, and fibrotic burden. Concurrently, they downregulate cardiac NLRP3 inflammasome components, namely pro-caspase-1 and p20, and both of which can demonstrate the substantial potential of biomimetic coating strategies for optimizing resveratrol’s therapeutic performance in myocardial infarction treatment.²⁷²

To specifically improve microvascular dysfunction while bypassing the therapeutic drawbacks of free allicin, neutrophil membrane-coated mesoporous silica nanoparticles have been engineered to improve the loading efficiency of allicin. This biomimetic platform leverages the innate inflammation-homing ability of neutrophils and specifically binds to hypoxia-reoxygenation-injured cardiac microvascular endothelial cells, restoring cardiac function through upregulating nitric oxide production, while inhibiting ferroptosis as evidenced by reduced cell death. In vivo, these nanoparticles led to significant improvements in ejection fraction and fractional shortening, accompanied by reductions in infarct size and myocardial fibrosis.¹⁰⁷

Moreover, to simultaneously enhance bioavailability and mitigate adverse effects, an innovative biomimetic nanoplatform encapsulating puerarin within a neutrophil membrane-coated polydopamine core has been developed, and this biomimetic approach leverages the inflammatory chemotaxis of neutrophil membranes to enable targeted delivery to the infarcted myocardium and significantly enhances accumulation at the MI site. In vivo evaluations confirm that this nanoplatform attenuates cardiomyocyte pyroptosis by targeting the NLRP3-CASP1-IL-1β/IL-18 signaling axis while concurrently modulating the inflammatory milieu via induction of M2 macrophage polarization, thereby ultimately enhancing cardiac function.²⁷³

Ischemic Stroke (IS)

IS triggers an inflammatory response characterized by rapid immune cell infiltration, representing both a challenge and an opportunity for targeted therapeutic intervention. Neutrophils are among the first responders, for they can infiltrate the brain by adhering to activated endothelial cells via ligands like Mac-1 and LFA-1, thereby exacerbating BBB dysfunction and promoting clot formation through NETs.²⁷⁴ Likewise, macrophages and microglia infiltrate the ischemic brain within a few hours. These cells exhibit a dynamic phenotypic shift, where the initially protective, anti-inflammatory M2 phenotype is later dominated by the pro-inflammatory M1 phenotype, which triggers neuroinflammation and neuronal dysfunction. This natural homing capability of immune cells has been ingeniously leveraged for biomimetic nanotherapies. For instance, macrophage membrane coatings enable accurate drug delivery to ischemic lesions and can carry large molecular weight drugs across the compromised BBB.²⁷⁵ Microglia membrane coatings, especially from the M2 phenotype, not only home to the ischemia-damaged BBB but also facilitate the secretion of anti-inflammatory cytokines and promote the repolarization of pro-inflammatory M1 microglia.¹¹⁶ To create more sophisticated targeting systems, hybrid approaches such as combining platelet and neutrophil membranes have been developed. These hybrid cell membrane can hijack neutrophils, neutralize proinflammatory cytokines, and suppress NETs formation. Beyond immune cells, MSC membranes have been used to reduce immunogenicity and enhance homing to the ischemic penumbra, showing a four fold higher accumulation and remarkable efficacy in reducing cerebral infarction volume.²⁷⁶

To tackle the complex pathophysiology of IS, advanced nanoplatforms are being designed to achieve targeted drug delivery with controlled release. A key therapeutic goal is scavenging ROS and mitigating oxidative damage. Compared to free drugs, platelet membrane coatings alone achieved a 63% reduction in ischemic area and a 72% reduction in ROS levels.⁴¹ Another innovative approach employs “shield and sword” nano-soldiers composed of monocyte membrane-coated rapamycin nanoparticles. These constructs actively target inflamed endothelial cells, inhibit monocyte adhesion, and then traverse the endothelium to release their anti-inflammatory cargo.³⁹ Achieving precise spatiotemporal control of drug release is equally essential. To address this, Yu et al engineered a melanin nanoparticle (MNP) system that undergoes photothermal-mediated membrane rupture upon exposure to near-infrared (NIR) irradiation. This facilitates tissue plasminogen activator (tPA) release for rapid thrombolysis and allows the neuroprotective agents to subsequently reach the infarction site to prevent reperfusion injury, thus fulfilling the dual requirement of rapid recanalization and intelligent neuroprotection.²⁷⁷

However, achieving simultaneous thrombolysis and neuroprotection does not fully address the persistent and self-amplifying inflammatory response driven by microglial dysregulation. To overcome this limitation by actively reprogramming the immune milieu, an innovative biomimetic nanoplatform has been developed, which encapsulates baicalin within a PLGA core and envelops it with an M2 macrophage membrane. This design imparts immune-evasive characteristics that extend systemic circulation while simultaneously enabling active targeting to inflamed brain microvascular endothelial cells via integrin α4 and VCAM-1 interaction, and achieves significant accumulation in the ipsilateral ischemic brain tissue where it is preferentially taken up by injured neurons and microglia. By promoting the polarization of microglia from the pro-inflammatory M1 phenotype towards the anti-inflammatory M2 phenotype, attenuating neutrophil infiltration, and inhibiting neuronal apoptosis through regulation of the Bax/Bcl-2 pathway, this novel strategy demonstrates excellent neuroprotective efficacy against MIRI while simultaneously reducing infarct volume and improving neurological function.²⁷⁸

This neuroprotection effect is further expanded by a dual-loaded liposomal system carrying paeonol and polymetformin, which employs a hybrid tumor-platelet membrane to overcome the restrictive blood-brain barrier. In vitro studies have shown that the preserved membrane proteins enabled efficient BBB penetration, enhanced uptake by inflamed endothelial cells and neurons, and provided immune evasion via CD47. In vivo studies have also indicated the prolonged circulation and superior accumulation in ischemic brain tissue for up to 24 hours. Moreover, in terms of therapeutic outcomes, it diminished infarct volume, alleviated cerebral edema, and restored neurological function. This hybrid membrane strategy offers a promising approach for precise IS treatment.²⁷⁹

Moving beyond single-pathway interventions, the therapeutic window can be further targeted through multi-monomer synergistic engineering, as demonstrated by platelet membrane-mimetic nanocarriers incorporating curcumin and tideglusib. These biomimetic vehicles actively target the ischemic brain to facilitate caveolin-dependent transcytosis into the deep parenchyma, where the synchronous action of curcumin and tideglusib efficiently scavenges localized reactive oxygen species and stimulates neuroprotective cytokine secretion through interlocking redox and cellular regulatory mechanisms to mitigate reperfusion injury.²⁸⁰

The pharmaceutical effects of these TCM monomers towards AS, thrombus, MI and IS are summarized in Tables 5–8, while the disadvantages, the cell membrane coating, and their main effects in improving therapeutic efficacy, are summarized in Table 9. Their structural formula and the pathogenesis of AS, thrombus, MI and IS are summarized in Figures 3–7.

Table 5.

TCM Monomers Combined with Cell Membrane Nanotechnology in the Treatment of AS

TCM Monomer	Classification	Anti-Inflammation	Lipid Metabolism	Oxidative Stress	Refs
Ginsenoside Rb1	Tetracyclic triterpenoid saponin	- Activate glucocorticoid receptor - Suppress NF-κB/MAPK - Reduce IL-1β, IL-6, TNF-α	- Via M2 polarization	- Activate SIRT1 and AMPK - Upregulate eNOS and NO - Promote Nrf2 nuclear translocation - Upregulate antioxidant enzymes	[144–148]
Colchicine	Tropolone alkaloid	- Suppress NLRP3 inflammasome - Inhibit NETs formation and neutrophil chemotaxis - Increase IL-10 and TGF-β	- Via inflammation reduction	- Reduce superoxide production via microtubule disruption	[149–152]
Artemisinin	Sesquiterpene lactone	- Inhibit NLRP3 inflammasome in macrophages - Block monocyte adhesion	- Activate AMPK/mTOR/ULK1 pathway - Promote macrophage autophagy - Inhibit foam cell formation	- Activate SOD - Reduce MDA and caspase 3/7 - Activate PI3K/Akt/eNOS - Increase NO	[155–160]
Proanthocyanidin	Polymeric flavonoid	- Downregulate P-selectin, ICAM-1, VCAM-1, MCP-1 - Suppress TNF-α-induced adhesion molecule expression	- Downregulate LOX-1 - Disrupt CRP-oxLDL interaction	- Directly prevent LDL oxidation - Downregulate LOX-1 - Protect endothelium	[162–164]
Berberine	Isoquinoline alkaloid	- Activate PPARγ - Reduce SASP-related inflammation - Modulate gut microbiota	- Reduce intestinal cholesterol absorption via LDLR/PCSK9 - Increase hepatic cholesterol turnover via AMPK - Upregulate ABCA1, ABCG1 for cholesterol efflux - Downregulate FASN, SREBP1 for lipid synthesis	- Upregulate HO-1 - Reduce ROS accumulation in macrophages	[167–172]

Table 6.

TCM Monomers Combined with Cell Membrane Nanotechnology in the Treatment of Thrombus

TCM Monomer	Classification	Anti-Inflammation	Thrombolysis	Refs
Lumbrokinase	Enzyme	- Regulate macrophage polarization - Upregulate manganese-dependent SOD	- Direct fibrin degradation - Convert plasminogen to active plasmin - Reduce blood viscosity - Inhibit platelet function, prolong PT and aPTT - Promote VEGF production and endothelial cell migration	[176–179]
Hirudin	Peptide	- Inhibit apoptosis, improve vascular endothelial function	- Bind to thrombin - Block thrombin-mediated fibrinogen cleavage and fibrin formation - Inhibit thrombus-bound thrombin	[183–185]
Ginsenoside Rg1	Tetracyclic triterpenoid saponin	- Inhibit NF-κB and TLR4/NF-κB/NLRP3 pathways	- Suppress platelet aggregation and adhesion - Reduce thrombin-fibrinogen binding - Modulate platelet PKC-MAPK pathway	[188,189]

Table 7.

TCM Monomers Combined with Cell Membrane Nanotechnology in the Treatment of MI

TCM Monomer	Classification	Anti-Inflammation	Cardioprotection	Oxidative Stress	Refs
Berberine	Isoquinoline alkaloid	- Suppress PI3K/Akt signaling - Promote M2 macrophage polarization in infarcted heart	- Inhibit apoptosis - Address mitochondrial dysfunction - Inhibit fibroblast-to-myofibroblast conversion, reduce ECM deposition	- Reduce myocardial superoxide generation and MDA levels - Increase SOD activity	[192–199]
Resveratrol	Polyphenol	- Inhibit lymphocyte-derived IL-2, IFN-γ - Suppress macrophage-derived TNF-α, IL-12	- Regulate autophagy - Inhibit ferroptosis - Counteract cardiac fibrosis - Protect endothelial cells	- Strong free radical scavenging capacity	[200–203]
Allicin	Organosulfur compound	- Mitigate NLRP3 inflammasome activation - Modulate gut microbiota	- Maintain Ca2+ homeostasis - Enhance Ca2+ reuptake and removal - Reverse Ca[2]2+ overload-induced apoptosis - Promote vasorelaxation	- Modulate redox via thiol group interactions - Reduce ROS accumulation	[206–212]
Puerarin	Isoflavone	- Inhibit M1, increase M2 - Reduce TLR4 signaling	- Reduce ER stress - Promote angiogenesis - Promote NO/eNOS expression for coronary recanalization	- Reduce serum MDA and CK - Increase SOD activity	[215–221]

Table 8.

TCM Monomers Combined with Cell Membrane Nanotechnology in the Treatment of IS

TCM Monomer	Classification	Anti-Inflammation	Neuroprotection	Oxidative Stress	Refs
Baicalin	Flavonoid	- Suppress astrocyte activation - Inhibit M1 - Regulate SIRT1/HMGB1 pathway in microglia - Suppress miR-181b/HMGB1/TLR4/NF-κB axis - Upregulate TREM2 receptors	- Preserve mitochondrial function - Activate BDNF-TrkB pathway - Inhibit ferroptosis - Anti-apoptosis	- Reduce oxidative stress, restore ATP	[226–230]
Paeonol	Phenolic compound	- Inhibit microglia activation - Reduce accumulation of TLR2-, TLR4-, IL-1β-positive cells at infarct sites - Reduce reactive astrogliosis and glial scar formation	- Reduce TUNEL-positive cells - Suppress cytosolic AIF accumulation and mitochondrial Bax expression - Preserve BBB integrity	- Suppress and scavenge superoxide anions - Phase II enzyme induction - Activate pAkt/Nrf2/HO-1 pathway	[232–236]
Curcumin	Polyphenol	- Inhibit NLRP3 inflammasome - Reduce GSDMD+, caspase-1+ microglia/macrophages - Downregulate GSDMD-N, cleaved caspase-1, NLRP3 - Inhibit M1 - Promote microglial M2 polarization	- Reduce hippocampal neuron atrophy - Improve mitochondrial function - Reverse calcium overload	- Scavenge ROS	[239–246]

Table 9.

Improvements in the Therapeutic Efficacy of TCM Monomers Due to Cell Membrane Nanotechnology

TCM Monomer	Disease	Disadvantages of Free Drugs	Cell Membrane Coating	Key Improvements with Nanoparticles	Refs
Ginsenoside Rb1	AS	- Poor bioavailability and off-target effects. - Limited targeting to atherosclerotic plaques. - Systemic administration leads to accumulation in non-target sites.	Platelet membrane	- Plaque reduction: Reduced plaque area in aortic arch from 85% to 20% - Block cell adhesion: Block HUVEC and U937 cell adhesion by 85% - Promote lipid efflux: Decreased LDL-c, TG, TC levels; Increased HDL-c level	[255]
Colchicine (COL)	AS	- Narrow therapeutic window (ED50/LD50 risk) - Severe side effects at clinical doses (0.5–1 mg/day) - Poor accumulation in atherosclerotic plaques	Macrophage membrane	- Immune evasion: 2.24× fold lower macrophage uptake - Enhanced targeting: Stronger plaque accumulation - Therapeutic effects: Plaque area reduced to 31.41%, collagen increased to 52.80%	[256]
Artemisinin (ART) and Procyanidins (PC)	AS	- Rapid drug clearance - Low bioavailability - Limited targeting to plaque - Systemic side effects	Macrophage + RBC membrane	- Prolonged circulation: t1/2 increase from 2.672h to 4.619 h - Enhanced plaque targeting: Elevated fluorescence intensity within the aortic arch and abdominal aorta - Reduced lesion area: From 29.95% to 8.99% - Lower inflammation: Decreased serum concentrations of IL-6, TNF-α, IL-1β	[257]
Berberine (BBR)	AS	- Poor oral bioavailability (<1%) - Low water solubility - Rapid elimination - Poor targeting to atherosclerotic plaques	M2 macrophage membrane	- Targeting: Enhanced accumulation in aortic plaques - Anti-inflammatory: Downregulation of TNF-α, IL-6; Upregulation of IL-10 - Plaque reduction: Diminished lipid accumulation with enhanced collagen deposition	[281]
Lumbrokinase (LBK)	Thrombus	- Rapid elimination, short half-life - High doses required and bleeding risk - Narrow therapeutic index	Platelet membrane	- Targeting ability: Stronger binding ability to fibrin and platelet-rich clots - Thrombolysis efficacy: Increase from 2.4×105 U/kg to 8×104 U/kg - Reduced bleeding risk: Tail bleeding time and fibrinogen levels remained near normal	[262]
Recombinant Hirudin (rH)	DVT	- High bleeding risk - Short half-life - Non-specific distribution - Organ toxicity at high doses	Platelet membrane	- Longer half-life: Enhanced blood retention - Targeted thrombus accumulation: Increase fluorescence to 1.64–5.11 fold - Reduced bleeding time: Shorter than free drugs	[263]
Ginsenoside Rg1	Thrombus	- Low oral bioavailability, short half-life. - Lack of targeting ability to thrombus sites. - Risk of systemic bleeding with conventional antithrombotic drugs.	Erythrocyte + platelet membrane	- Thrombus inhibition: Reach 88.20% - Promote coagulation: Increase Blood Coagulation Index to 51.94% - ROS scavenging and anti-inflammatory effects	[264]
Berberine (BBR)	MI	- Low intestinal absorption and oral bioavailability (less than 0.4%). - Intravenous administration causes transient hypotension. - Poor accumulation in infarcted myocardium.	Platelet membrane	- Targeted accumulation: Enrich in infarcted myocardium with sustained release over 20 days - Lower inflammation and cell apoptosis: Increase CD206+ and reduce TUNEL+ - Improve cardiac function: Enhance LVEF and reduce collagen deposition	[271,282]
Resveratrol (RES)	MI	- poor systemic bioavailability (less than 1% in plasma) due to extensive first-class metabolism - Non-targeted distribution leading to systemic side effects - Simple PLGA nanoparticles quickly cleared by immune system	Macrophage membrane	- Targeted accumulation: 1.5× higher fluorescence in infarcted myocardium - Improved cardiac function: 1.46× fold higher EF and 1.56× fold higher FS - Better tissue repair: Effective reduction in infarct size and fibrosis	[272,283]
Allicin (AL)	MIRI	- Sequestered by interactions with fatty acids and proteins in the plasma membrane, thereby compromising therapeutic potential. - Poor pharmacokinetics, suboptimal bioavailability, quick inactivation, premature elimination. - Insufficient targeting to injured heart.	Neutrophil membrane	- Improve cardiac function: Increase LVEF from 28.3% to 60.2% - Reduce Infarct size: From 31.4% to 16.8% - Targeted accumulation: Stronger fluorescent signal in heart - Ferroptosis inhibition: Reduce ptgs2 mRNA expression and oxidative stress markers	[107]
Puerarin (PU)	MI	- Systemic side effects (rash, fever, anaphylaxis) - Poor targeting to infarct area - Low local concentration	Neutrophil membrane	- Targeted delivery: Stronger fluorescence in infarcted heart at 24 h - Reduced cardiomyocyte apoptosis: Lower TUNEL+ cells - Improved cardiac function: Higher ejection fraction - Reduced fibrosis: Lower collagen I/III ratio	[273]
Baicalin (BA)	IS	- Poor BBB penetration - poor intestinal permeability and low oral availability (about 2.2%) - Limited accumulation in ischemic brain	M2 macrophage membrane	- Brain targeting: Higher fluorescence in ischemic brain Pharmacokinetics: Extended circulation time Therapeutic efficacy: Reduced infarct volume, improved neurological scores	[278,284]
Paeonol (PAE)	IS	- BBB prevents most drugs from reaching the brain. - Poor lesion targeting, rapid clearance by immune system. - Limited neuroprotection and anti-inflammatory effects.	Platelet + 4T1 cell membrane	- BBB penetration and targeting: Stronger fluorescence in brain - Infarct volume: Reduce from 32.9% to 8.5% - Neuroprotection: Cell viability increased from 34.6% to significantly higher levels - Anti-inflammatory: Reduced ROS, increased M2 microglia polarization, decreased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).	[279]
Curcumin (Cur)	IS	- extremely low oral bioavailability (less than 1% in human), poor solubility - chemical instability - limited intestinal permeability, rapid systemic elimination - Cannot cross blood-brain barrier effectively	Platelet membrane	- Brain targeting: 2.6–4.2× fold higher accumulation in ischemic brain - Synergistic antioxidant: 3.9× fold lower ROS - Stroke recovery: Reduce infarct volume to 16.08% and improve mNSS score	[247,280]

Figure 3.

TCM monomers used in cell membrane-coating nanotechnology.

Figure 4.

The pathogenesis of AS (Purple square: platelet membrane target; Green square: RBC membrane target; Blue square: macrophage membrane target; Brown square: neutrophil membrane target; Red square: monocyte membrane target; Black arrow: lead to; Red T arrow: inhibit).

Figure 5.

The pathogenesis of thrombus ((a) Oxidative stress; (b) Inflammation; (c) Platelet aggregation; (d) Fibrin formation) (Purple square: platelet membrane target; Green square: RBC membrane target; Blue square: macrophage membrane target; Brown square: neutrophil membrane target; Red square: monocyte membrane target; Black arrow: lead to; Red T arrow: inhibit).

Figure 6.

The pathogenesis of MI (Purple square: platelet membrane target; Green square: RBC membrane target; Blue square: macrophage membrane target; Brown square: neutrophil membrane target; Red square: monocyte membrane target; Black arrow: lead to; Red T arrow: inhibit).

Figure 7.

The pathogenesis of IS (Purple square: platelet membrane target; Green square: RBC membrane target; Blue square: macrophage membrane target; Brown square: neutrophil membrane target; Red square: monocyte membrane target; Black arrow: lead to; Red T arrow: inhibit).

Future Perspectives and Challenges

Of the over 45 different nanoparticle types, including liposomes, polymeric nanoparticles, micelles, albumin-bound nanoparticles, and inorganic nanoparticles in more than 80 clinical trials, three have received regulatory approval from the FDA, EMA, or CE Mark.²⁸⁵ This demonstrates the clinical potential of nanomedicine, where drug encapsulation within nanocarriers enhances therapeutic effectiveness while reducing metabolism and toxicity compared to conventional pharmacokinetics where dose increases typically raise both efficacy and toxicity.¹¹⁰

Future Perspectives

Recently, genetic engineering has become a powerful tool for modifying cell membranes to optimize cell membrane-coated nanoparticles. By inducing or upregulating specific surface markers, researchers can enhance nanoparticle performance. For instance, Krishnan used viral transduction to anchor SpyCatcher on membrane surfaces, enabling covalent attachment of SpyTag-labeled ligands. They conjugated three distinct targeting ligands, including a DARPin, an affibody, and a single-chain variable fragment, to SpyCatcher-expressing cell membrane-coated nanoparticles. When delivering docetaxel, these nanoparticles showed enhanced cytotoxicity in vitro and improved tumor suppression in vivo. This modular design allows a single base formulation to be adapted for different ligands without re-engineering the membrane, accelerating the development of cell membrane-coated nanoparticles.²⁸⁶ Similarly, Deng genetically engineered chondrocytes to overexpress interleukin-1 receptor type 2 (IL-1R2) on the membrane, enabling nanoparticles to target extracellular IL-1β and intracellular mitochondrial SIRT3 simultaneously for synergistic effects.²⁸⁷ To achieve further adaptability, a small peptide Asn-Gly-Arg (NGR) was expressed onto red blood cell membranes using in vivo CRISPR. This peptide targets a specific aminopeptidase N isoform on cancer cells. These membranes coated onto oleanolic acid nanoparticles significantly increased tumor accumulation and growth inhibition in APN-expressing tumors compared to uncoated controls.²⁸⁸

With advances in computing and AI, computational modeling is now popular for designing drug delivery systems, including processes like fusion, lipid rearrangement, and membrane penetration. Dissipative particle dynamics (DPD) simulates nanoparticle transport in blood and interactions with vascular walls, helping predict the circulation of these nanoparticles. DPD also showed that zwitterionic polymer-coated nanoparticles attach more strongly to cell membranes under low pH due to charge conversion, relevant for targeting and immune evasion.²⁸⁹ Monte Carlo (MC) simulations study drug release from lipid domains and pore formation in liposomes, offering insights into cargo release upon membrane interaction. Physiologically based pharmacokinetic (PBPK) modeling predicts absorption, distribution, metabolism, excretion, tissue-specific accumulation, and clearance by the mononuclear phagocyte system.²⁹⁰

To ensure high yields and low immunogenicity, autologous cells are increasingly used in personalized nanoparticle design. This customized approach tailors nanoparticles to the patient’s disease type, receptor profile, and immune status, moving beyond one-size-fits-all.²⁹¹ Patient-derived membranes enhance biocompatibility, avoid immune detection, and retain parental cell targeting.¹¹⁰ Whole cells like red blood cells, stem cells, and immune cells preserve intrinsic functions such as long circulation, site-specific migration, and barrier crossing. Notably, autologous stem cells leverage tumor-tropic properties to deliver therapeutics directly into the tumor microenvironment, offering personalized cancer therapy.²⁹² For example, Xu showed that nanoparticles coated with patient-derived cancer cell membranes present a broad spectrum of autologous tumor antigens, activating polyclonal CD4⁺ and CD8⁺ T cell responses and reducing immune escape. These membranes also naturally contain damage-associated molecular patterns and heat shock proteins, acting as endogenous danger signals that enhance dendritic cell maturation and cross-presentation without external adjuvants.²⁹³

The evolution of multi-functional theranostic nanoparticles has also driven the development of cell membrane coating nanotechnology, which enables prolonged circulation, active targeting, biocompatibility, and scalable manufacturing. When combined with microfluidic electroporation, this approach improves coating integrity and facilitates personalized medicine. Based on this, Rao et al used microfluidic electroporation to synthesize RBC membrane-coated magnetic nanoparticles for enhanced MRI-guided photothermal therapy of cancer. The Fe₃O₄ core provides MRI contrast and NIR photothermal conversion, while the RBC shell prolongs circulation and promotes tumor accumulation via the EPR effect.²⁹⁴ Similarly, other cell membranes have been applied to tumor imaging. For instance, cancer cell membranes enable self-targeting for multimodality imaging. Macrophage membranes leverage inflammatory attraction for UCL imaging. Platelet membranes exploit platelet-tumor interactions for deep photoacoustic imaging. Stem cell membranes use homing ability for FL/MRI/CT imaging. Bacterial membranes offer rigid, scalable structures for MRI. Moreover, hybrid membranes combine long circulation with homologous targeting for PA-guided therapy.⁹³ In addition to the treatment and diagnosis of cancer, these nanoparticles have also shown increased extravasation and macrophage uptake at sites of inflammation, such as atherosclerotic plaques or infarcted heart tissue, where they accumulate in endo-lysosomes and release their iron oxide cargo upon coating degradation, enabling site-specific CVD imaging.⁷²

Despite these advances, clinical experience shows regulatory approval depends more on precise distribution, chemical stability, and predictable safety. For organic soft nanoformulations, patisiran successfully overcomes nucleic acid instability and rapid blood clearance. In a pivotal Phase III trial, its lipid nanoparticle carrier protected fragile oligonucleotides from blood enzymes, using ionizable cationic lipids to release the drug inside liver cells and achieve sustained reduction of toxic serum proteins.²⁹⁵ For inorganic nanodrugs, crystalline hafnium oxide nanoparticle NBTXR3 demonstrates the value of local physical activation. With a specific size and stabilized surface phosphate coating, these inert particles remain fixed within soft-tissue tumors after a single local injection. Due to hafnium’s high atomic number and electron density, the particles amplify radiotherapy energy, generating localized reactive oxygen species and DNA double-strand breaks. This doubled the complete response rate without increasing systemic side effects.²⁹⁶

Challenges

However, multiple biological and manufacturing barriers must be addressed before widespread clinical translation becomes feasible. The cell membrane coating itself presents unique immunological challenges despite biosafety evaluations of nanoparticle cores. Immune responses may be triggered by surface microorganisms, such as viruses, bacteria, toxins, and pyrogens, and additional immunogenicity concerns arise from the presence of major histocompatibility complex (MHC) molecules.⁸ It can also be induced by the heterogeneous composition of diverse cell types, which may result in the generation of anti-nanoparticle antibodies, thereby provoking inflammation and tissue damage, a phenomenon termed “pathological” autoimmunity. When autoantibodies bind to self-antigens, they can promote target cell destruction, trigger cell activation, and form antigen-antibody complexes. These complexes then deposit in tissues, provoking inflammation that may ultimately damage tissues and organs. The integrity of the coating process can also affect the resulting immune response, as incomplete coating may result in exposure of the synthetic core, which can in turn trigger undesired immune reactions.²⁹⁷ These factors necessitate can both improve quality control measures and consideration of autologous cell membrane sources to minimize antigenic risks. Hybrid membranes can also be designed to retain necessary targeting ligands while minimizing immunostimulatory components, achieving an optimal balance between efficient targeting and long circulation.

Nanoparticle design parameters significantly influence biological behavior and therapeutic efficacy. Elasticity affects immune evasion and targeting, soft nanoparticles exhibit superior circulation time due to reduced macrophage uptake, while stiff nanoparticles demonstrate enhanced target accumulation and cellular internalization. Surface potential, particularly higher zeta potential, improves stability through electrostatic repulsion that minimizes aggregation and off-target effects. Size and shape further modulate immune responses, with larger particles eliciting stronger immunoglobulin production and spiky nanostructures showing distinct immunomodulatory properties.²⁹⁸

The transition from characterization in aqueous solutions to biological environments introduces additional complexities. Nanoparticles experience shear stress from high protein and ion concentrations, potentially causing colloidal instability and toxicity.²⁹⁹ Furthermore, administration routes and patient-specific plasma microenvironments create substantial variability in nanoparticle behavior, complicating therapeutic effect quantification across different disease states.

Manufacturing challenges present the most significant barriers to clinical translation. Resource scarcity and inefficient membrane extraction techniques limit scale-up potential. While akaryotic cells like red blood cells and platelets require established protocols for sufficient blood supplies, nucleated cell membranes need development of mass culture techniques and high-throughput processing methods.¹⁰ Microfluidic technology offers promise for standardizing production, though donor cell type and cell cycle stage variations cause batch-to-batch efficacy differences.³⁰⁰ Furthermore, to address the issue of functional limitations, genetic editing can also be applied to engineer customized cell membranes, expanding the range of potential nanoformulations while surpassing the capabilities attainable with natural cell membranes.³⁰¹

The production process itself faces multiple obstacles. Extraction methods are complex with inconsistent standards, resulting in poor reproducibility. Biological membrane instability compared to synthetic materials further complicates manufacturing. The enormous cell requirements, up to 3 × 10⁹ platelets to coat just 1 mg of PLGA nanoparticles, highlight the need for simplified, high-yield production methods. Risks of bacterial contamination, especially for platelets stored at 22–24°C over a period of 5–7 days, can pose further challenges.³⁰²

From a regulatory perspective, cell membrane-coated nanoparticles pose distinct safety and quality control challenges, creating an inherent conflict between cGMP sterility requirements and CMC quality attributes. While cGMP mandates terminal sterilization for intravenous injectables, such techniques inevitably denature the functional surface proteins of the cell membrane. Under CMC guidelines, this degradation undermines the biomimetic targeting mechanism and may trigger immunogenic changes, leading to out-of-specification rejections. Moreover, cell membrane-coated nanoparticles straddle the boundary between synthetic nanomedicines and complex biomaterials, occupying a regulatory void without tailored guidance frameworks. Consequently, these platforms are subject to the most conservative, multi-disciplinary evaluation standards, resulting in prolonged scrutiny, higher costs, and delayed market authorization.

The ultimate goal of drug development is clinical application, so it is crucial to address the challenges associated with clinical translation. Due to the huge gap between uniform animal models and complex human biology, there still exists a high failure rate for nanomedicines to enter human trials. Current data reviews show that the success rate for cancer formulations moving into phase is only 14.3%.³⁰³ The primary biological barrier limiting clinical translation is massive liver clearance, where approximately 30%~99% of the injected dose is rapidly trapped by the liver.³⁰⁴ Mechanistic studies show that this clearance is driven not only by Kupffer cells, but also by liver sinusoidal endothelial cells that actively take up circulating nanoparticles via surface receptors, a process accelerated by a sharp drop in blood flow speed within the tiny blood vessels of the liver. Furthermore, human translation is severely blocked by the dense fibrotic tissues and irregular blood vessel networks common in human tumors, which prevent uniform nanoparticle penetration and make the traditional enhanced permeability and retention effect highly inconsistent in human patients.³⁰⁵ These biological barriers explain the failure of several clinical trials. For example, the prostate-specific membrane antigen-targeted polymeric nanoparticle BIND-014 failed to show a better safety-to-efficacy profile in humans over free drugs, and the polymeric micelle NK105 failed because its passive tumor accumulation via the enhanced permeability and retention effect did not result in superior clinical outcomes in human patients.³⁰³ Together, these historical lessons demonstrate that overcoming translation barriers requires shifting research focus away from overly complex active-targeting designs toward stable, reproducible formulations that optimize patient safety, controlled drug ratios, and large-scale manufacturing compliance.

Conclusion

In summary, cell membrane-coated nanoparticles exhibit exceptional potential as sophisticated delivery systems for TCM monomers in CVD therapy. These TCM monomers demonstrate diverse pharmacological activities, including anti-inflammatory, antioxidant, and anti-apoptotic effects. However, their clinical application has been hindered by poor solubility, low bioavailability, and rapid clearance. By harnessing the intrinsic properties of natural cell membranes, cell membrane-coated nanoparticles can significantly improve the bioavailability and targeted delivery of TCM monomers while simultaneously mitigating off-target effects. This novel nanotechnology successfully addresses key limitations of conventional TCM monomer therapy, enabling more effective multi-targeted treatment of complex cardiovascular conditions. Nevertheless, before clinical translation can be achieved, several critical challenges must be addressed, including manufacturing scalability, production method efficiency, long-term safety, and regulatory concerns. Therefore, to ensure better efficacy and safety, future efforts should prioritize the development of standardized fabrication protocols, optimizing cell membrane sources, and establishing comprehensive safety evaluation systems. We hope that this review can lay a more solid foundation for research on the integration of TCM and cell membrane-coated nanotechnology.

Funding Statement

This study was supported by grants from the National Natural Science Foundation of China (No 82204737), the Science and Technology Commission of Shanghai Municipality (No 24ZR1465300), the Health Commission of Shanghai Municipality (ZY(2021-2023)-0203-04), Future Plan for Traditional Chinese Medicine Inheritance and Development of Shanghai Municipal Hospital of Traditional Chinese Medicine (WLJH2021ZY-ZYY007; WL-HBBD-2021001K), Traditional Chinese Medicine Research Project of Hongkou District Health Commission (HKZYY-2024-06), Medical Research Project of Hongkou District Health Commission (HongWei 2402-03).

Disclosure

The authors declare no conflict of interest.