Key Takeaways & Executive Findings
- •• • Hybrid cell membrane-lipid nanoparticles (CM-LNPs) integrate natural membrane proteins with synthetic phospholipids, achieving synergistic retention of biological functions (e.g., immune evasion, homing) and synthetic advantages (e.g., tunable surface chemistry), as evidenced by references to RBC membrane-coated liposomes (Ferrel et al., ACS Appl Bio Mater, 2021) and tumor cell-derived vesicle-coated nanocarriers (Bose et al., ACS Nano, 2018). • • Microfluidic fabrication offers precise control over nanoparticle size and surface properties, overcoming batch-to-batch variability inherent in extrusion and ultrasonication, which is critical for scalable clinical production (reference to microfluidics-prepared ultra-small biomimetic nanovesicles for brain tumor targeting, Wang et al., 2021). • • Cell membrane biomimetic nanoparticles exhibit prolonged systemic circulation and enhanced target site accumulation via self-recognition mechanisms, with RBC membranes providing superior biocompatibility and high drug loading capacity, as demonstrated in studies on ferrimagnetic nanochain-engineered mesenchymal stem cells for post-stroke recovery (Zhang et al., Adv Funct Mater, 2019, 29:1900603). • • The homing effect of cell membranes, mediated by surface receptors responding to pathological signals, is leveraged for targeted delivery; for example, ICAM-1 functions as an efferocytosis receptor in inflammatory macrophages (Wiesolek et al., Am J Pathol, 2020, 190:874–885), and IL-1β enhances MSC adhesion via LFA-1/ICAM-1 interaction (Wu et al., Stem Cells Int, 2019), enabling inflammation-targeted delivery.
Abstract
The continuous advancement of bionanomaterial technology has driven significant strategic transformations in the design and fabrication of biomimetic nanocarriers. This review systematically traces the evolution from single-cell membrane nanovesicles to hybrid cell membrane nanovesicles integrating multiple cell membranes, culminating in cell membrane hybrid lipid nanoparticles (CM-LNPs) that combine natural cell membranes or membrane proteins with engineered synthetic phospholipids. This technological progression enables the synergistic retention of multicellular biological functions while incorporating advantageous synthetic material properties, such as enhanced engineering flexibility and surface modifiability. The article critically evaluates the advantages and limitations of traditional extrusion and ultrasonication methods for preparing cell membrane nanovesicles, highlighting the benefits and development prospects of novel microfluidic techniques in CM-LNP fabrication. Furthermore, it explores future application prospects and challenges of CM-LNPs in the biomedical field, particularly in drug delivery systems and precision medicine. The review underscores the potential of CM-LNPs to overcome clinical limitations of conventional liposomes, such as poor stability, rapid drug leakage, and inadequate targeting, by leveraging the natural homing effect of cell membranes and the tunability of synthetic lipids. Emphasis is placed on the role of microfluidics in achieving precise, scalable, and reproducible fabrication, which is critical for clinical translation. The abstract synthesizes current knowledge and identifies key research gaps, offering a forward-looking perspective on the engineering of biomimetic nanoparticles for advanced therapeutic applications.
1. Introduction
Conventional liposomal drug delivery systems, despite their structural similarity to cell membranes and superior biocompatibility, suffer from poor physicochemical stability, rapid drug leakage, short circulation half-life, and inadequate targeting specificity. These limitations have hindered their clinical translation, particularly for complex diseases such as cancer and inflammatory disorders. The integration of functional biopolymers and cell membrane coatings has emerged as a promising strategy to address these bottlenecks, yet early approaches using single-cell membranes often fail to replicate the multifactorial interactions required for effective targeting and immune evasion.
This review addresses the critical need for next-generation biomimetic nanocarriers by systematically advancing from single-cell membrane nanovesicles to hybrid cell membrane nanovesicles and ultimately to cell membrane hybrid lipid nanoparticles (CM-LNPs). By fusing natural cell membranes with synthetic phospholipids, CM-LNPs synergistically combine the biological functionality of source cells—such as homing and immune evasion—with the engineering flexibility of synthetic materials. Furthermore, the adoption of microfluidic fabrication techniques offers precise, scalable, and reproducible production, overcoming the limitations of traditional extrusion and ultrasonication. This technological evolution directly tackles the clinical and industrial bottlenecks of poor stability, low targeting efficiency, and manufacturing inconsistency, paving the way for precision medicine applications.
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Qi Liu, Yang Liu, Li Qiao, Shiqi Chang, Xiafeng Peng, Ning-Ping Huang (2026). Engineering Revolution of Cell Membrane-Biomimetic Nanoparticles: From Hybridization Strategy Innovation to Microfluidics-Enabled Precision Fabrication. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3740-y
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Frequently Asked Questions
What are the specific advantages of microfluidic fabrication over traditional extrusion and ultrasonication for CM-LNP production, and how does it impact scalability and reproducibility?
Microfluidic fabrication enables precise control over nanoparticle size, size distribution, and surface properties through tunable flow rates and mixing ratios, achieving batch-to-batch reproducibility that is critical for clinical translation. Unlike extrusion and ultrasonication, which often yield heterogeneous populations and suffer from scale-up limitations, microfluidics offers continuous, scalable production with minimal batch variability. For instance, microfluidics-prepared ultra-small biomimetic nanovesicles have demonstrated enhanced brain tumor targeting (Wang et al., 2021), indicating superior control over particle characteristics. This precision is essential for regulatory approval and industrial-scale manufacturing.
How do CM-LNPs overcome the rapid drug leakage and poor stability issues of conventional liposomes, and what empirical evidence supports this?
CM-LNPs integrate natural cell membranes, which provide a robust barrier and self-recognition proteins that reduce opsonization and premature clearance, thereby enhancing stability and prolonging circulation. For example, red blood cell membrane-coated liposomes have shown high drug loading capacity and maintained bioactive compound stability (Ferrel et al., 2021). The membrane's semi-permeable nature and surface proteins contribute to reduced drug leakage. Additionally, the hybrid lipid composition allows for tunable membrane fluidity, further stabilizing the encapsulated payload. These properties are empirically validated in studies demonstrating prolonged systemic circulation and enhanced target site accumulation.
What are the key challenges in scaling up CM-LNP production from laboratory to industrial scale, and how does microfluidics address these bottlenecks?
Traditional methods like extrusion and ultrasonication are batch processes with limited scalability, high energy consumption, and poor control over particle uniformity, leading to batch-to-batch variability. Microfluidics offers continuous, high-throughput production with precise control over mixing and self-assembly, enabling consistent particle size and surface functionalization. This scalability is crucial for meeting clinical and commercial demands. However, challenges remain in optimizing microfluidic chip design for large-volume production and ensuring the stability of biological membranes during processing. Ongoing research focuses on addressing these issues to facilitate industrial adoption.
How do CM-LNPs achieve targeted delivery to specific pathological sites, and what role does the homing effect play?
CM-LNPs inherit surface receptors from source cells that recognize and bind to ligands overexpressed at pathological sites, such as tumors or inflamed tissues. This homing effect is exemplified by ICAM-1, which functions as an efferocytosis receptor in inflammatory macrophages (Wiesolek et al., 2020), and LFA-1/ICAM-1 interactions that enhance mesenchymal stem cell adhesion under inflammatory conditions (Wu et al., 2019). By incorporating membranes from cells with natural tropism, CM-LNPs can actively navigate to target tissues, improving therapeutic efficacy and reducing off-target effects. This active targeting is a significant advantage over passive accumulation via the EPR effect.
What are the potential clinical applications of CM-LNPs beyond drug delivery, and what evidence supports their versatility?
CM-LNPs are not limited to drug delivery; they can be engineered for diagnostic imaging, theranostics, and immunotherapy. For instance, tumor cell-derived extracellular vesicle-coated nanocarriers have been used for cancer-specific delivery of anti-miR-21 and imaging agents (Bose et al., 2018), demonstrating their theranostic potential. Additionally, fusogenic nanoparticles have been employed for siRNA delivery and immunogene therapy, modulating macrophage responses to bacterial infections (Kim et al., 2018, 2019). These applications highlight the platform's versatility, leveraging the natural functions of source cells to achieve multifunctional capabilities in precision medicine.
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