Natural Cell Membranes Research Articles

Enhanced Targeting, Retention, and Penetration of Amphotericin B Through a Biomimetic Strategy to Treat Against Vulvovaginal Candidiasis

AbstractAn effective therapeutic strategy to treat vulvovaginal candidiasis (VVC) that is mainly caused by Candida albicans (C. albicans) infection is highly desirable. While Amphotericin B (AmB) has demonstrated promise, its precise localization to C. albicans burden at vaginal sites is oftentimes limited by the high fluidity microenvironment of the vagina, which can compromise treatment efficacy. To overcome this issue, a biomimetic AmB delivery system is developed, in which AmB preloaded polymeric cores are cloaked with vaginal epithelial cells membrane (VM‐ANP). With its cell membrane coating, VM‐ANP naturally targets and strongly binds with C. albicans, thus resisting the self‐cleaning of vaginal fluid. Besides its long retention property, VM‐ANP could penetrate deeply in vaginal tissue to achieve its full antifungal potential by attaching to hidden C. albicans. It is shown that both C. albicans suspension and biofilm biomass could be effectively inhibited by the VM‐ANP in vitro. In a C. albicans intravaginal infection model, treatment with VM‐ANP results in significantly decreased fungal challenges both in vaginal tissue and fluid. Overall, such biomimetic strategy adds the merit of natural cell membrane into the targeted delivery of drug in treating VVC, which also serves as a promising platform against vaginitis‐related pathogens.

Using Cell Membranes as Recognition Layers to Construct Ultrasensitive and Selective Bioelectronic Affinity Sensors.

Conventional sandwich immunosensors rely on antibody recognition layers to selectively capture and detect target antigen analytes. However, the fabrication of these traditional affinity sensors is typically associated with lengthy and multistep surface modifications of electrodes and faces the challenge of nonspecific adsorption from complex sample matrices. Here, we report on a unique design of bioelectronic affinity sensors by using natural cell membranes as recognition layers for protein detection and prevention of biofouling. Specifically, we employ the human macrophage (MΦ) membrane together with the human red blood cell (RBC) membrane to coat electrochemical transducers through a one-step process. The natural protein receptors on the MΦ membrane are used to capture target antigens, while the RBC membrane effectively prevents nonspecific surface binding. In an attempt to detect tumor necrosis factor alpha (TNF-α) cytokine using the bioelectronic affinity sensor, it demonstrates a remarkable limit of detection of 150 pM. This new sensor design integrates natural cell membranes and electronic transduction, which offers synergistic functionalities toward a broad range of biosensing applications.

Fibroblast-Mimicking nanodecoys for Multi-Target antiangiogenesis in the inflammation treatment

Localized inhibition of angiogenesis is an attractive therapeutic strategy for exogenous mediators-induced inflammation. Here, inspired by the unique biointerface of the natural cell membrane, we develop an endogenous cell membrane-derived biomimetic nanosystem (fibroblast membrane-camouflaged nanoparticles, FB@NPs) for blocking angiogenesis in the lipopolysaccharides (LPS)-induced inflammatory process. The fibroblast membrane coating provides as-fabricated nanoparticles with potent and specific binding ability to LPS, diverting these pathological toxins away and protecting resident fibroblasts. By efficient LPS neutralization and elimination, FB@NPs inhibit the production of a number of cross-regulated pro-angiogenic factors, and thereby greatly block inflammatory neovascularization. Besides, due to the self-recognition capability and inherent remarkable biocompatibility of these endogenous biomimetic nanoparticles, FB@NPs show highly desirable biosafety during the antiangiogenesis process in inflammation treatment. In summary, the novel exploration provides a promising route for developing next-generation biomimetic antiangiogenic nanoplatform.

Biomimetic semiconducting polymer dots for highly specific NIR-II fluorescence imaging of glioma

Glioma with very short medium survival time consists of 80% of primary malignant types of brain tumors. The unique microenvironment such as the existence of the blood-brain barrier (BBB) makes the glioma theranostics exhibit low sensitivity in diagnosis, a poor prognosis and low treatment efficacy. Therefore, the development of multifunctional nanoplatform that can cross BBB and target the glioma is essential for the high-sensitivity detection and ablation of cancer cells. In this study, C6 cell membrane-coated conjugated polymer dots (Pdots-C6) were constructed for targeted glioma tumor detection. As a new kind of biomimetic and biocompatible nanoprobes, Pdots-C6 preserve the complex biological functions of natural cell membranes while possessing physicochemical properties for NIR-II fluorescence imaging of glioma. After encapsulating C6 cell membrane on the surface of conjugated Pdots, Pdots-C6 exhibited the most favorable specific targeting capabilities in vitro and in vivo. In particular, this pilot study demonstrates that biomimetic nanoparticles offer a potential tool to enhance specific targeting to the brain, hence improving glioma tumor detection accuracy.

Inimitable Impacts of Ceramides on Lipid Rafts Formed in Artificial and Natural Cell Membranes

Ceramide is the simplest precursor of sphingolipids and is involved in a variety of biological functions ranging from apoptosis to the immune responses. Although ceramide is a minor constituent of plasma membranes, it drastically increases upon cellular stimulation. However, the mechanistic link between ceramide generation and signal transduction remains unknown. To address this issue, the effect of ceramide on phospholipid membranes has been examined in numerous studies. One of the most remarkable findings of these studies is that ceramide induces the coalescence of membrane domains termed lipid rafts. Thus, it has been hypothesised that ceramide exerts its biological activity through the structural alteration of lipid rafts. In the present article, we first discuss the characteristic hydrogen bond functionality of ceramides. Then, we showed the impact of ceramide on the structures of artificial and cell membranes, including the coalescence of the pre-existing lipid raft into a large patch called a signal platform. Moreover, we proposed a possible structure of the signal platform, in which sphingomyelin/cholesterol-rich and sphingomyelin/ceramide-rich domains coexist. This structure is considered to be beneficial because membrane proteins and their inhibitors are separately compartmentalised in those domains. Considering the fact that ceramide/cholesterol content regulates the miscibility of those two domains in model membranes, the association and dissociation of membrane proteins and their inhibitors might be controlled by the contents of ceramide and cholesterol in the signal platform.

Construction of Biomimetic-Responsive Nanocarriers and their Applications in Tumor Targeting.

At present, tumors are leading cause of death. Biomimetic nanocarriers for precision cancer therapy are attracting increasing attention. Nanocarriers with a good biocompatible surface could reduce the recognition and elimination of nanoparticles as foreign substances by the immune system, offer specific targeting, and improve the efficacy of precision medicine for tumors, thereby providing outstanding prospects for application in cancer therapy. In particular, cell membrane biomimetic camouflaged nanocarriers have become a research hotspot because of their excellent biocompatibility, prolonged circulation in the blood, and tumor targeting. The objective of this study is to summarize the biological targeting mechanisms of different cell membraneencapsulated nanocarriers in cancer therapy. In this article, the characteristics, applications, and stages of progress of bionic encapsulated nanocarriers for different cell membranes are discussed, as are the field's developmental prospects. The findings on the characteristics of bionic encapsulated nanocarriers for different cell membranes and tumor treatment have been analyzed and summarized. Biomimetic nanosystems based on various natural cell and hybrid cell membranes have been shown to efficiently control targeted drug delivery systems. They can reduce immune system clearance, prolong blood circulation time, and improve drug loading and targeting, thereby enhancing the diagnosis and treatment of tumors and reducing the spread of CTCs. With advances in the development of biomimetic nanocarrier DDSs, novel ideas for tumor treatment and drug delivery have been emerged. However, there are still some problems in biomimetic nanosystems. Therefore, it needs to be optimized through further research, from the laboratory to the clinic to benefit a wide range of patients.

Advancements in cell membrane camouflaged nanoparticles: A bioinspired platform for cancer therapy.

The idea of employing natural cell membranes as a coating medium for nanoparticles (NPs) endows man-made vectors with natural capabilities and benefits. In addition to retaining the physicochemical characteristics of the NPs, the biomimetic NPs also have the functionality of source cell membranes. It has emerged as a promising approach to enhancing the properties of NPs for drug delivery, immune evasion, imaging, cancer-targeting, and phototherapy sensitivity. Several studies have been reported with a multitude of approaches to reengineering the surface of NPs using biological membranes. Owing to their low immunogenicity and intriguing biomimetic properties, cell-membrane-based biohybrid delivery systems have recently gained a lot of interest as therapeutic delivery systems. This review summarises different kinds of biomimetic NPs reported so far, their fabrication aspects, and their application in the biomedical field. Finally, it briefs on the latest advances available in this biohybrid concept.

The dynamical Matryoshka model: 3. Diffusive nature of the atomic motions contained in a new dynamical model for deciphering local lipid dynamics

In accompanying papers [Bicout et al., BioRxiv https://doi.org/10.1101/2021.09.21.461198 (2021); Cissé et al., BioRxiv https://doi.org/10.1101/2022.03.30.486370 (2022)], a new model called Matryoshka model has been proposed to describe the geometry of atomic motions in phospholipid molecules in bilayers and multilamellar vesicles based on their quasielastic neutron scattering (QENS) spectra. Here, in order to characterize the relaxational aspects of this model, the energy widths of the QENS spectra of the samples were analyzed first in a model-free way. The spectra were decomposed into three Lorentzian functions, which are classified as slow, intermediate, and fast motions depending on their widths. The analysis provides the diffusion coefficients, residence times, and geometrical parameters for the three classes of motions. The results corroborate the parameter values such as the amplitudes and the mobile fractions of atomic motions obtained by the application of the Matryoshka model to the same samples. Since the current analysis was carried out independently of the development of the Matryoshka model, the present results enhance the validity of the model. The model will serve as a powerful tool to decipher the dynamics of lipid molecules not only in model systems, but also in more complex systems such as mixtures of different kinds of lipids or natural cell membranes.

Membrane Cholesterol Depletion Enhances Enzymatic Activity of Cell‐Membrane‐Coated Metal‐Organic‐Framework Nanoparticles

AbstractMetal‐organic‐framework nanoparticles (MOF NPs) have been increasingly used to encapsulate therapeutic enzymes for delivery. To better interface these MOF NPs with biological systems, researchers have coated them with natural cell membranes, enabling biomimicking properties suitable for innovative biomedical applications. Herein, we report that the enzymatic activity of cell‐membrane‐coated MOF NPs can be significantly enhanced by reducing membrane cholesterol content. We demonstrate such cholesterol‐enzymatic activity correlation using zeolitic imidazolate framework‐8 MOF NPs to encapsulate catalase, horseradish peroxidase, and organophosphate hydrolase, respectively. MOF NPs coated with membranes of human red blood cells or macrophages show similar outcomes, illustrating the broad applicability of this finding. The mechanistic investigation further reveals that reducing cholesterol levels effectively enhances membrane permeability likely responsible for the increased enzymatic activity. These results also imply a facile approach to tailoring the enzymatic activity of cell‐membrane‐coated MOF NPs by simply tuning the membrane cholesterol level.

Membrane Cholesterol Depletion Enhances Enzymatic Activity of Cell-Membrane-Coated Metal-Organic-Framework Nanoparticles.

Metal-organic-framework nanoparticles (MOF NPs) have been increasingly used to encapsulate therapeutic enzymes for delivery. To better interface these MOF NPs with biological systems, researchers have coated them with natural cell membranes, enabling biomimicking properties suitable for innovative biomedical applications. Herein, we report that the enzymatic activity of cell-membrane-coated MOF NPs can be significantly enhanced by reducing membrane cholesterol content. We demonstrate such cholesterol-enzymatic activity correlation using zeolitic imidazolate framework-8 MOF NPs to encapsulate catalase, horseradish peroxidase, and organophosphate hydrolase, respectively. MOF NPs coated with membranes of human red blood cells or macrophages show similar outcomes, illustrating the broad applicability of this finding. The mechanistic investigation further reveals that reducing cholesterol levels effectively enhances membrane permeability likely responsible for the increased enzymatic activity. These results also imply a facile approach to tailoring the enzymatic activity of cell-membrane-coated MOF NPs by simply tuning the membrane cholesterol level.

Intravenous Delivery of Living Listeria monocytogenes Elicits Gasdmermin-Dependent Tumor Pyroptosis and Motivates Anti-Tumor Immune Response.

The facultative intracellular bacterium Listeria monocytogenes (Lmo) has great potential for development as a cancer vaccine platform given its properties. However, the clinical application of Lmo has been severely restricted due to its rapid clearance, compromised immune response in tumors, and inevitable side effects such as severe systemic inflammation after intravenous administration. Herein, an immunotherapy system was developed on the basis of natural red blood cell (RBC) membranes encapsulated Lmo with selective deletion of virulence factors (Lmo@RBC). The biomimetic Lmo@RBC not only generated a low systemic inflammatory response but also enhanced the accumulation in tumors due to the long blood circulation and tumor hypoxic microenvironment favoring anaerobic Lmo colonization. After genome screening of tumors treated with intravenous PBS, Lmo, or Lmo@RBC, it was first found that Lmo@RBC induced extensive pore-forming protein gasdermin C (GSDMC)-dependent pyroptosis, which reversed immunosuppressive tumor microenvironment and promoted a systemic strong and durable anti-tumor immune response, resulting in an excellent therapeutic effect on solid tumors and tumor metastasis. Overall, Lmo@RBC, as an intravenous living bacterial therapy for the selective initiation of tumor pyrolysis, provided a proof-of-concept of live bacteria vaccine potentiating tumor immune therapy.

Engineered Cell Membrane-Derived Nanocarriers: The Enhanced Delivery System for Therapeutic Applications.

There has been a rapid development of biomimetic platforms using cell membranes as nanocarriers to camouflage nanoparticles for enhancing bio-interfacial capabilities. Various sources of cell membranes have been explored for natural functions such as circulation and targeting effect. Biomedical applications of cell membranes-based delivery systems are expanding from cancer to multiple diseases. However, the natural properties of cell membranes are still far from achieving desired functions and effects as a nanocarrier platform for various diseases. To obtain multi-functionality and multitasking in complex biological systems, various functionalized modifications of cell membranes are being developed based on physical, chemical, and biological methods. Notably, many research opportunities have been initiated at the interface of multi-technologies and cell membranes, opening a promising frontier in therapeutic applications. Herein, the current exploration of natural cell membrane functionality, the design principles for engineered cell membrane-based delivery systems, and the disease applications are reviewed, with a special focus on the emerging strategies in engineering approaches.

Design and simulation of the liposomal model by using a coarse-grained molecular dynamics approach towards drug delivery goals

The simulated liposome models provide events in molecular biological science and cellular biology. These models may help to understand the cell membrane mechanisms, biological cell interactions, and drug delivery systems. In addition, the liposomes model may resolve specific issues such as membrane transports, ion channels, drug penetration in the membrane, vesicle formation, membrane fusion, and membrane protein function mechanism. One of the approaches to investigate the lipid membranes and the mechanism of their formation is by molecular dynamics (MD) simulations. In this study, we used the coarse-grained MD simulation approach and designed a liposome model system. To simulate the liposome model, we used phospholipids that are present in the structure of natural cell membranes (1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)). Simulation conditions such as temperature, ions, water, lipid concentration were performed based on experimental conditions. Our results showed a liposome model (ellipse vesicle structure) during the 2100 ns was formed. Moreover, the analysis confirmed that the stretched and ellipse structure is the best structure that could be formed. The eukaryotic and even the bacterial cells have elliptical and flexible structures. Usually, an elliptical structure is more stable than other assembled structures. The results indicated the assembly of the lipids is directed through short-range interactions (electrostatic interactions and, van der Waals interactions). Total energy (Van der Waals and electrostatic interaction energy) confirmed the designed elliptical liposome structure has suitable stability at the end of the simulation process. Our findings confirmed that phospholipids DOPC and DOPE have a good tendency to form bilayer membranes (liposomal structure) based on their geometric shapes and chemical-physical properties. Finally, we expected the simulated liposomal structure as a simple model to be useful in understanding the function and structure of biological cell membranes. Furthermore, it is useful to design optimal, suitable, and biocompatible liposomes as potential drug carriers.

A Light-Driven Integrated Bio-Capacitor with Single Nano-Channel Modulation

Bioelectronics, an emerging discipline formed by the biology and electronic information disciplines, has maintained a state of rapid development since its birth. Amongst the various functional bioelectronics materials, bacteriorhodopsin (bR), with its directional proton pump function and favorable structural stability properties, has drawn wide attention. The main contents of the paper are as follows: Inspired by the capacitive properties of natural protoplast cell membranes, a new bio-capacitor based on bR and artificial nanochannels was constructed. As a point of innovation, microfluidic chips were integrated into our device as an ion transport channel, which made the bio-capacitor more stable. Meanwhile, a single nanopore structure was integrated to improve the accuracy of the device structure. Experiments observed that the size of the nanopore affected the ion transmission rate. Consequently, by making the single nanopore’s size change, the photocurrent duration time (PDT) of bR was effectively regulated. By using this specific phenomenon, the original transient photocurrent was successfully transformed into a square-like wave.

An erythrocyte membrane-camouflaged biomimetic nanoplatform for enhanced chemo-photothermal therapy of breast cancer.

Nano drug delivery systems are a research hotspot in the field of tumor therapy. In this work, molybdenum disulfide (MoS2) nanosheets were selected as the base material and a natural red blood cell membrane (RBC membrane) was camouflaged on the nanosheets to enhance their dispersibility and tumor targeting profile. The camouflaged molybdenum disulfide nanocomposites (MoS2-RBC) were successfully prepared by incubation. This nanomaterial has good stability and biocompatibility with a good immune evasion ability. MoS2 has a large specific surface area and unique layered structure, which provides favorable conditions for the loading of anticancer drugs. Adriamycin hydrochloride (DOX) was used as the model drug and the drug loading capacity was 98.98%. In the tumor microenvironment, the red cell membrane modified MoS2 drug delivery system (MoS2-RBC-DOX) showed obvious pH-dependent release behavior. In addition, the excellent photothermal properties of MoS2 are conducive to the release of drugs, thus improving the efficacy. According to the cell tests, MoS2-RBC had no cytotoxicity toward tumor cells, while DOX loading induced dose-dependent cytotoxicity. Furthermore, MoS2-RBC has a favorable photothermal effect, and chemotherapy combined with photothermal therapy is more effective than any single therapy. In vivo fluorescence imaging and in vivo photothermal imaging experiments confirmed the promoted accumulation of carrier materials at the tumor site after RBC membrane modification. Finally, in vivo antitumor studies showed that photothermal/chemotherapy combined with MoS2-RBC could completely inhibit tumor growth, and the body weights of mice fluctuated within the normal range without significant decrease. In summary, this MoS2-RBC drug delivery system provides a safe, rapid and effective option for future treatment of breast cancer.

Lung cell membrane-coated nanoparticles capable of enhanced internalization and translocation in pulmonary epithelial cells

Cell membrane-coated nanoparticles (CMCNP), which involve coating a core nanoparticle (NP) with cell membranes, have been gaining attention due to their ability to mimic the properties of the cells, allowing for enhanced delivery and efficacy of therapeutics. Two CMCNP systems comprised of an acetalated dextran-based NP core loaded with curcumin (CUR) coated with cell membranes derived from pulmonary epithelial cells were developed. The NP were approximately 200 nm and their surface charges varied based on their coating, where CMCNP systems exhibited negative surface charge like natural cell membranes. The NP were smooth, spherical, and homogeneous with distinct coatings on their cores. Minimal in vitro toxicity was observed for the NP and controlled release of CUR was observed. The CMCNP internalized into and translocated across an in vitro pulmonary epithelial monolayer significantly more than the control NP. Blocking endocytosis pathways reduced the transcytosis of NP, indicating a relationship between endocytosis and transcytosis. These newly developed CMCNP have the potential to be used in pulmonary drug delivery applications to potentially enhance NP internalization and transport into and across the pulmonary epithelium.

Synthetic Cell as a Platform for Understanding Membrane-Membrane Interactions.

In the pursuit of understanding life, model membranes made of phospholipids were envisaged decades ago as a platform for the bottom-up study of biological processes. Micron-sized lipid vesicles have gained great acceptance as their bilayer membrane resembles the natural cell membrane. Important biological events involving membranes, such as membrane protein insertion, membrane fusion, and intercellular communication, will be highlighted in this review with recent research updates. We will first review different lipid bilayer platforms used for incorporation of integral membrane proteins and challenges associated with their functional reconstitution. We next discuss different methods for reconstitution of membrane fusion and compare their fusion efficiency. Lastly, we will highlight the importance and challenges of intercellular communication between synthetic cells and synthetic cells-to-natural cells. We will summarize the review by highlighting the challenges and opportunities associated with studying membrane–membrane interactions and possible future research directions.

Tumor microenvironment-activated cancer cell membrane-liposome hybrid nanoparticle-mediated synergistic metabolic therapy and chemotherapy for non-small cell lung cancer

BackgroundBiomimetic nanotechnology-based RNA interference (RNAi) has been successful in improving theranostic efficacy in malignant tumors. Its integration with hybrid biomimetic membranes made of natural cell membranes fused with liposomal membranes is mutually beneficial and extends their biofunctions. However, limited research has focused on engineering such biomimetics to endow them with unique properties and functions, in particular, those essential for a “smart” drug delivery system, such as a tumor microenvironment (TME)-activated multifunctional biomimetic nanoplatform.ResultsHerein, we utilized an integrated hybrid nanovesicle composed of cancer cell membranes (Cm) and matrix metallopeptidase 9 (MMP-9)-switchable peptide-based charge-reversal liposome membranes (Lipm) to coat lipoic acid-modified polypeptides (LC) co-loaded with phosphoglycerate mutase 1 (PGAM1) siRNA (siPGAM1) and DTX. The nanovesicle presented a negatively charged coating (citraconic anhydride-grafted poly-l-lysine, PC) in the middle layer for pH-triggered charge conversion functionalization. The established chemotherapeutic drug (DTX) co-delivery system CLip-PC@CO-LC nanoparticles (NPs) have a particle size of ~ 193 nm and present the same surface proteins as the Cm. Confocal microscopy and flow cytometry results indicated a greater uptake of MMP-9-treated CLip-PC@CO-LC NPs compared with that of the CLip-PC@CO-LC NPs without MMP-9 pretreatment. The exposure to MMP-9 activated positively charged cell-penetrating peptides on the surface of the hybrid nanovesicles. Moreover, pH triggered membrane disruption, and redox triggered DTX and siRNA release, leading to highly potent target-gene silencing in glycolysis and chemotherapy with enhanced antiproliferation ability. The biodistribution results demonstrated that the CLip-PC@LC-DiR NPs accumulated in the tumor owing to a combination of long blood retention time, homologous targeting ability, and TME-activated characteristics. The CLip-PC@CO-LC NPs led to more effective tumor growth inhibition than the DTX and free siPGAM1 formulations.ConclusionsTME-activated cancer cell membrane-liposome integrated hybrid NPs provide an encouraging nanoplatform that combines RNAi with chemotherapy for precise treatment of non-small cell lung cancer.Graphical abstract

Cell Membrane Vesicles with Enriched CXCR4 Display Enhances Their Targeted Delivery as Drug Carriers to Inflammatory Sites.

Cell membrane vesicles (CMVs) are composed of natural cell membranes which makes them effective drug delivery systems with low immunogenicity and prolonged circulation time. However, targeting delivery of CMVs in vivo for clinical applications is still a major challenge. In this study, CXCR4 recombinant lentivirus is transfected into MC‐3T3 cells and membrane CXCR4‐enriched MC‐3T3 cells are obtained. CMVs with enriched membrane CXCR4 display (CXCR4‐CMVs) are obtained from the transfected MC‐3T3 cells. Curcumin, an effective natural anti‐inflammatory compound, is encapsulated into CXCR4‐CMVs through physical entrapment (CXCR4/Cur‐CMVs), with the membrane integrity of CXCR4/Cur‐CMVs being well‐preserved. CXCR4/Cur‐CMVs induce enhanced M2 macrophage polarization, exhibit anti‐inflammatory effects, and significantly improve homing via the CXCR4/CXCL12 axis in vitro. Utilizing ulcerative colitis and apical periodontitis as inflammatory disease models, it is found that CXCR4/Cur‐CMVs are obviously aggregated within inflammatory areas after intravenous administration, which results in significant amelioration of ulcerative colitis and apical periodontitis. Therefore, this research may provide a feasible and innovative approach for fabricating an inflammatory site‐targeting delivery system, by engineering CMVs to increase membrane‐presenting CXCR4 receptor.

Preparation and Characterization of Anti-Cancer Crystal Drugs Based on Erythrocyte Membrane Nanoplatform.

The simple and functional modification of the nanoparticle’s surface is used to efficiently deliver chemotherapeutic drugs for anti-cancer treatment. Here, we construct a nanocrystalline drug delivery system with doxorubicin wrapped in red blood cell membranes for the treatment of mouse breast cancer models. Compared with traditional free drug treatments, the biodegradable natural red blood cell membrane is combined with pure crystalline drugs. The nanoparticles obtained by the preparation method have superior properties, such as good stability, significantly delaying the release of drugs and enhancing the inhibitory effect on tumor cells. This study shows that the design of RBC as an outsourced drug delivery system provides a promising foundation for the continued development, clinical trials, and nanomedicine research of anti-cancer drug nanocarriers in the future.