Membrane-coated Nanoparticles Research Articles

Immunocyte membrane-derived biomimetic nano-drug delivery system: a pioneering platform for tumour immunotherapy.

Tumor immunotherapy characterized by its high specificity and minimal side effects has achieved revolutionary progress in the field of cancer treatment. However, the complex mechanisms of tumor immune microenvironment (TIME) and the individual variability of patients' immune system still present significant challenges to its clinical application. Immunocyte membrane-coated nanocarrier systems, as an innovative biomimetic drug delivery platform, exhibit remarkable advantages in tumor immunotherapy due to their high targeting capability, good biocompatibility and low immunogenicity. In this review we summarize the latest research advances in biomimetic delivery systems based on immune cells for tumor immunotherapy. We outline the existing methods of tumor immunotherapy including immune checkpoint therapy, adoptive cell transfer therapy and cancer vaccines etc. with a focus on the application of various immunocyte membranes in tumor immunotherapy and their prospects and challenges in drug delivery and immune modulation. We look forward to further exploring the application of biomimetic delivery systems based on immunocyte membrane-coated nanoparticles, aiming to provide a new framework for the clinical treatment of tumor immunity.

Microfluidics-enabled mesenchymal stem cell derived Neuron like cell membrane coated nanoparticles inhibit inflammation and apoptosis for Parkinson’s Disease

Parkinson’s disease (PD) is the second largest group of neurodegenerative diseases, and its existing drug treatments are not satisfactory. Natural cell membrane drugs are used for homologous targeting to enhance efficacy. In this study, microfluidic electroporation chip prepared mesenchymal stem cell-derived neuron-like cell membrane-coated curcumin PLGA nanoparticles (MM-Cur-NPs) was synthesized and explored therapeutic effect and mechanism in PD. MM-Cur-NPs can protect neuron from damage, restore mitochondrial membrane potential and reduce oxidative stress in vitro. In PD mice, it also can improve movement disorders and restore damaged TH neurons. MM-Cur-NPs was found to be distributed in the brain and metabolized with a delay within 24 h. After 1 h administration, MM-Cur-NPs were distributed in brain with a variety of neurotransmitters were significantly upregulated, such as dopamine. Differentially expressed genes of RNA-seq were enriched in the inflammation regulation, and it was found the up-expression of anti-inflammatory factors and inhibited pro-inflammatory factors in PD. Mechanically, MM-Cur-NPs can not only reduce neuronal apoptosis, inhibit the microglial marker IBA-1 and inflammation, but also upregulate expression of neuronal mitochondrial protein VDAC1 and restore mitochondrial membrane potential. This study proposes a therapeutic strategy provide neuroprotective effects through MM-Cur-NPs therapy for PD.

Effect of Polymer and Cell Membrane Coatings on Theranostic Applications of Nanoparticles: A Review.

The recent decade has witnessed a remarkable surge in the field of nanoparticles, from their synthesis, characterization, and functionalization to diverse applications. At the nanoscale, these particles exhibit distinct physicochemical properties compared to their bulk counterparts, enabling a multitude of applications spanning energy, catalysis, environmental remediation, biomedicine, and beyond. This review focuses on specific nanoparticle categories, including magnetic, gold, silver, and quantum dots (QDs), as well as hybrid variants, specifically tailored for biomedical applications. A comprehensive review and comparison of prevalent chemical, physical, and biological synthesis methods are presented. To enhance biocompatibility and colloidal stability, and facilitate surface modification and cargo/agent loading, nanoparticle surfaces are coated with different synthetic polymers and very recently, cell membrane coatings. The utilization of polymer- or cell membrane-coated nanoparticles opens a wide variety of biomedical applications such as magnetic resonance imaging (MRI), hyperthermia, photothermia, sample enrichment, bioassays, drug delivery, etc. With this review, the goal is to provide a comprehensive toolbox of insights into polymer or cell membrane-coated nanoparticles and their biomedical applications, while also addressing the challenges involved in translating such nanoparticles from laboratory benchtops to in vitro and in vivo applications. Furthermore, perspectives on future trends and developments in this rapidly evolving domain are provided.

Current Strategies and Therapeutic Applications of Mesenchymal Stem Cell-Based Drug Delivery.

Mesenchymal stem cells (MSCs) have emerged as a promising approach for drug delivery strategies because of their unique properties. These strategies include stem cell membrane-coated nanoparticles, stem cell-derived extracellular vesicles, immunomodulatory effects, stem cell-laden scaffolds, and scaffold-free stem cell sheets. MSCs offer advantages such as low immunogenicity, homing ability, and tumor tropism, making them ideal for targeted drug delivery systems. Stem cell-derived extracellular vesicles have gained attention for their immune properties and tumor-homing abilities, presenting a potential solution for drug delivery challenges. The relationship between MSC-based drug delivery and the self-renewal and differentiation capabilities of MSCs lies in the potential of engineered MSCs to serve as effective carriers for therapeutic agents while maintaining their intrinsic properties. MSCs exhibit potent immunosuppressive functions in MSC-based drug delivery strategies. Stem cell-derived EVs have low immunogenicity and strong therapeutic potential for tissue repair and regeneration. Scaffold-free stem cell sheets represent a cutting-edge approach in regenerative medicine, offering a versatile platform for tissue engineering and regeneration across different medical specialties. MSCs have shown great potential for clinical applications in regenerative medicine because of their ability to differentiate into various cell types, secrete bioactive factors, and modulate immune responses. Researchers are exploring these innovative approaches to enhance drug delivery efficiency and effectiveness in treating various diseases.

Cell membrane-coated nanoparticles in disease therapy

Nanotechnology has attracted increasing attention in the field of medical applications due to its significant potential for development. However, one major challenge that has emerged with nanoparticles is their tendency to activate the host immune clearance system, which hampers the achievement of desired therapeutic outcomes and may lead to harmful side effects. In recent years, membrane-coated nanoparticles have emerged as a promising solution, demonstrating their effectiveness in evading immune system clearance. These innovative nanoparticles inherit essential biological attributes from natural cell membranes, such as anchoring proteins and antigens. Consequently, membrane-coated nanoparticles exhibit unique capabilities such as immune evasion, prolonged circulation, targeted drug release, and immune modulation, substantially enhancing their versatility and prospects within the realm of biomedical applications. This review provides a comprehensive overview of the current applications of cell membrane-coated nanoparticles in disease therapy, highlighting their immense potential in this rapidly evolving platform. Additionally, the review outlines the promising prospects of this technology in disease therapy.

Biomimetic platelet-like nanoparticles enhance targeted hepatocellular carcinoma therapy

Curcumin (CUR) is a promising natural product for hepatocellular carcinoma (HCC) therapy. However, its clinical application has been limited by some issues such as rapid clearance and inadequate tumor accumulation. To address these drawbacks, we developed platelet membrane-coated CUR-loaded PLGA nanoparticles (PCPNPs). In this work, due to the bioinspired strategy, the PCPNPs exhibited immune evasion, prolonged circulation, and improved accumulation at tumor sites compared to the traditional CUR formulation. The superior tumor targeting of PCPNPs was likely due to the interactions between platelet P-selectin and tumoral CD44. Furthermore, both in vitro and in vivo assays revealed that the PCPNPs showed outstanding anticancer efficacy without obvious toxicity. Therefore, PCPNPs represent a biosafe and promising anti-tumor strategy, overcoming the limitations associated with CUR. These findings not only contribute to the advancement of natural compound nano-formulation but also open new avenues for targeted cancer treatment.

Macrophage membrane-coated nanoparticles for the treatment of infectious diseases.

Infectious diseases severely threaten human health, and traditional treatment techniques face multiple limitations. As an important component of immune cells, macrophages display unique biological properties, such as biocompatibility, immunocompatibility, targeting specificity, and immunoregulatory activity, and play a critical role in protecting the body against infections. The macrophage membrane-coated nanoparticles not only maintain the functions of the inner nanoparticles but also inherit the characteristics of macrophages, making them excellent tools for improving drug delivery and therapeutic implications in infectious diseases (IDs). In this review, we describe the characteristics and functions of macrophage membrane-coated nanoparticles and their advantages and challenges in ID therapy. We first summarize the pathological features of IDs, providing insight into how to fight them. Next, we focus on the classification, characteristics, and preparation of macrophage membrane-coated nanoparticles. Finally, we comprehensively describe the progress of macrophage membrane-coated nanoparticles in combating IDs, including drug delivery, inhibition and killing of pathogens, and immune modulation. At the end of this review, a look forward to the challenges of this aspect is presented.

A genetically engineered neuronal membrane-based nanotoxoid elicits protective immunity against neurotoxins

Given their dangerous effects on the nervous system, neurotoxins represent a significant threat to public health. Various therapeutic approaches, including chelating agents, receptor decoys, and toxin-neutralizing antibodies, have been explored. While prophylactic vaccines are desirable, it is oftentimes difficult to effectively balance their safety and efficacy given the highly dangerous nature of neurotoxins. To address this, we report here on a nanovaccine against neurotoxins that leverages the detoxifying properties of cell membrane-coated nanoparticles. A genetically modified cell line with constitutive overexpression of the α7 nicotinic acetylcholine receptor is developed as a membrane source to generate biomimetic nanoparticles that can effectively and irreversibly bind to α-bungarotoxin, a model neurotoxin. This abrogates the biological activity of the toxin, enabling the resulting nanotoxoid to be safely delivered into the body and processed by the immune system. When co-administered with an immunological adjuvant, a strong humoral response against α-bungarotoxin is generated that protects vaccinated mice against a lethal dose of the toxin. Overall, this work highlights the potential of using genetic modification strategies to develop nanotoxoid formulations against various biological threats.

Harnessing extracellular vesicle membrane for gene therapy: EVs-biomimetic nanoparticles

One of the main concerns in oligonucleotide-based therapeutics is achieving a successful cell targeting while avoiding drug degradation and clearance. Nanoparticulated drug delivery systems have emerged as a way of overcoming these issues. Among them, membrane-coated nanoparticles are of increasing relevance mainly due to their enhanced cellular uptake, immune evasion and biocompatibility. In this study, we designed and elaborated a simple and highly tuneable biomimetic drug delivery nanosystem based on a polymeric core surrounded by extracellular vesicles (EVs)-derived membranes. This strategy should allow the nanosystems to benefit from the properties conferred by the membrane proteins present in EVs membrane, key paracrine mediators. The developed systems were able to successfully encapsulate the required oligonucleotides. Also, their characterisation through already well standardised methods (dynamic light scattering, transmission electron microscopy and nanoparticle tracking analysis) and by fluorescence cross-correlation spectroscopy (FCCS) showed the desired core-shell structure. The cellular uptake using different cell types further confirmed the coating though an enhancement in cell internalisation of the developed biomimetic nanoparticles. This study brings up new possibilities for GapmeR delivery as it might be a base for the development of new delivery systems for gene therapy.

Engineered Cell Membrane-Coated Nanoparticles: New Strategies in Glioma Targeted Therapy and Immune Modulation.

Gliomas, the most prevalent primary brain tumors, pose considerable challenges due to their heterogeneity, intricate tumor microenvironment (TME), and blood-brain barrier (BBB), which restrict the effectiveness of traditional treatments like surgery and chemotherapy. This review provides an overview of engineered cell membrane technologies in glioma therapy, with a specific emphasis on targeted drug delivery and modulation of the immune microenvironment. This study investigates the progress in engineered cell membranes, encompassing physical, chemical, and genetic alterations, to improve drug delivery across the BBB and effectively target gliomas. The examination focuses on the interaction of engineered cell membrane-coated nanoparticles (ECM-NPs) with the TME in gliomas, emphasizing their potential to modulate glioma cell behavior and TME to enhance therapeutic efficacy. The review further explores the involvement of ECM-NPs in immunomodulation techniques, highlighting their impact on immune reactions. While facing obstacles related to membrane stability and manufacturing scalability, the review outlines forthcoming research directions focused on enhancing membrane performance. This review underscores the promise of ECM-NPs in surpassing conventional therapeutic constraints, proposing novel approaches for efficacious glioma treatment.

Abstract 134: Lesion-specific Suppression Of YAP/TAZ By Biomimetic Nanoparticles Ameliorates Atherosclerosis

Introduction: Recent evidence highlights the potential therapeutic benefit of targeting YAP/TAZ in mitigating atherosclerosis. However, challenges associated with systemic delivery hinder the translation of the mechanistic discovery into an effective treatment. This study aimed to address the challenges by developing a lesion-specific nanodrug to achieve site-specific inhibition of YAP/TAZ for atherosclerosis therapy. Hypothesis: We have formulated a novel monocyte membrane-coated nanoparticle (MoNP) platform designed to facilitate precise delivery of payloads to atherosclerotic arteries. Our hypothesis is that leveraging MoNP for the targeted delivery of verteporfin (VP), a potent YAP/TAZ inhibitor, will significantly enhance the efficacy in mitigating atherosclerosis. Methods: Polymeric nanoparticles containing VP were prepared using an emulsion approach, followed by enclosing them with plasma membranes isolated from monocytes, yielding MoNP-VP. The pharmacological effects of MoNP-VP were assessed on cultured vascular and immune cells, as well as in the atherosclerotic mouse model. Results: Our in vivo findings demonstrated that the administration of MoNP-VP, as opposed to free VP, led to a substantial reduction in arterial inflammation and plaque development, suggesting that VP delivered by MoNP is a more effective route than its free drug counterpart. To dissect the mechanisms of actions, we analyzed the arterial tissues post-treatment using scRNA-seq analysis. Our results identified 9 distinct cell clusters within the affected arteries. Specifically, MoNP-VP treatment led to a decrease in macrophage (MΦ) clusters and an increase in the cluster of smooth muscle cells (SMC). Furthermore, our in vitro assays confirmed the efficacies of MoNP-VP in reducing the atheroprone phenotypes. These include diminished endothelial cell activation, less proliferation and migration of SMC, and a reduction in foam cell formation from MΦ. Conclusion: Together, these findings support the notion that targeting YAP/TAZ dysregulation is a feasible strategy for reducing plaque development and progression and demonstrate that MoNP-VP is a highly effective nanodrug for treating atherosclerosis.

Research progress of cell membrane biomimetic nanoparticles for circulating tumor cells.

Early detection of cancer is crucial to reducing fatalities and improving patient outcomes. Metastasis is the first stage of aggressive cancers, often occurring before primary lesions can be seen. It occurs when cancerous cells disseminate to distant, non-malignant organs through the bloodstream, known as circulating tumor cells (CTCs). CTCs, or cancer tumor cells, are valuable indicators for predicting treatment response, metastasis progression, and disease progression. However, they are primarily used for research due to challenges like heterogeneity, separation from blood, and lack of clinical validation. Only a few methods have been approved for clinical use. One area of research is the isolation and identification of CTCs, which could significantly impact early cancer detection and prognosis. Current technologies using whole-blood samples use size, immunoaffinity, and density approaches, along with positive and negative enrichment techniques. Surface modification of nanomaterials is important for effective cancer therapies because it improves their ability to target and reduces interactions with healthy tissues. Consequently, researchers have created biomimetic nanoparticles covered with cell membranes using functional, targeted, and biocompatible coating technology. Nanoparticles with membranes can target specific cells, stay in circulation for longer, and avoid immune responses, which makes them much better at capturing CTCs. This study examines the current opportunities and difficulties associated with using cell membrane-coated nanoparticles as a capture technique for CTCs. In addition, we examine potential future developments in light of the current obstacles and investigate areas that require further research to fully understand its growing clinical possibilities.

Magnetic Nanoagent Coated with an Activated Macrophage Membrane for Colorimetric Detection of Bacteria.

The construction of cell mimics replicating the surface landscape and biological functions of the cell membrane offers promising prospects for biomedical research and applications. Inspired by the inherent recognition capability of immune cells toward pathogens, we have fabricated activated macrophage membrane-coated magnetic silicon nanoparticles (aM-MSNPs) in this work as an isolation and recognition tool for enhanced bacterial analysis. Specifically, the natural protein receptors on the activated macrophage membrane endow the MSNPs with a broad-spectrum binding capacity to different pathogen species. By further incorporation of a tyramide amplification strategy, direct naked-eye analysis of specific bacteria with a detection limit of 10 CFU/mL can be achieved. Moreover, application to the diagnosis of urinary tract infections has also been validated, and positive samples spiked with bacteria can be clearly distinguished with an accuracy of 100%. This work may enrich cell membrane-based architectures and provide an experimental paradigm for point-of-care testing (POCT) detection of bacteria.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

N-acetyl-L-cysteine-modified macrophage membrane-coated VEGF sustained-release nanoparticles for treatment of myocardial infarction: A biomimetic nano-buffer for neutralization of detrimental factors and promotion of mature angiogenesis

Myocardial infarction (MI) is a severe cardiovascular event arising from vascular thrombosis, causing cardiomyocyte fatality. Neovascularization, facilitated by Vascular Endothelial Growth Factor (VEGF), is a crucial therapy that delivers oxygen and nutrients to the surviving myocardium. After MI, a substantial influx of macrophages of the inflammatory phenotype infiltrates the infarcted myocardium. these macrophages secrete factors that exacerbate myocardial injury and orchestrate neovascular regression. A biomimetic nano-buffer system was developed in this study, consisting of VEGF-encapsulated nanoparticles coated with N-acetyl-L-cysteine (NAC)-modified macrophage membrane. These nanoparticles accumulate at the infarcted myocardium by exploiting the macrophage membrane's biomimetic inflammation chemotaxis. It effectively neutralizes detrimental factors in the infarcted myocardium while simultaneously enabling the controlled release of VEGF nanoparticles to promote angiogenesis within the affected tissue. What sets our research apart is the profound impact of the nano-buffer on macrophages, accomplished by its efficient scavenging of reactive oxygen species. This action triggers a vital response—the secretion of PDGF by macrophages—which significantly enhances the maturation of nascent blood vessels. The cumulative effect of these actions creates an exceptionally favorable milieu, fostering neovascularization. This study highlights the potential of the nano-buffer system in treating MI.

Revolutionizing Neurocare: Biomimetic Nanodelivery Via Cell Membranes.

Brain disorders represent a significant challenge in medical science due to the formidable blood-brain barrier (BBB), which severely limits the penetration of conventional therapeutics, hindering effective treatment strategies. This review delves into the innovative realm of biomimetic nanodelivery systems, including stem cell-derived nanoghosts, tumor cell membrane-coated nanoparticles, and erythrocyte membrane-based carriers, highlighting their potential to circumvent the BBB's restrictions. By mimicking native cell properties, these nanocarriers emerge as a promising solution for enhancing drug delivery to the brain, offering a strategic advantage in overcoming the barrier's selective permeability. The unique benefits of leveraging cell membranes from various sources is evaluated and advanced technologies for fabricating cell membrane-encapsulated nanoparticles capable of masquerading as endogenous cells are examined. This enables the targeted delivery of a broad spectrum of therapeutic agents, ranging from small molecule drugs to proteins, thereby providing an innovative approach to neurocare. Further, the review contrasts the capabilities and limitations of these biomimetic nanocarriers with traditional delivery methods, underlining their potential to enable targeted, sustained, and minimally invasive treatment modalities. This review is concluded with a perspective on the clinical translation of these biomimetic systems, underscoring their transformative impact on the therapeutic landscape for intractable brain diseases.

Ruxolitinib-loaded cytokine nanosponge alleviated the cytokine storm and dampened macrophage overactivation for the treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by a positive feedback loop between cytokine storm and macrophages and lymphocytes overactivation, which could serve as a valid therapeutic target for HLH treatment. In this study, the clinically extensively used JAK1/2 inhibitor ruxolitinib was encapsulated into macrophage membrane-coated nanoparticles (M@NP-R) with high drug-loading efficiency for targeted HLH treatment. In vitro and in vivo studies demonstrated that M@NP-R not only efficiently adsorbed extracellular proinflammation cytokines, like IFN-γ and IL-6 to alleviate the cytokine storm, but also effectively dampened macrophage activation and proliferation by intracellular JAK/STAT signaling pathway inhibition. M@NP-R treatment significantly ameliorated the clinical and laboratory manifestations of HLH in mouse models, including trilineage cytopenia, hypercytokinemia, organomegaly, hepatorenal dysfunction, and tissue inflammation. Importantly, M@NP-R significantly enhanced the survival of the lethal HLH mice. Altogether, M@NP-R successfully blocked the positive feedback loop between the cytokine storm and macrophage overactivation by depleting extracellular inflammatory cytokines and inhibiting the intracellular JAK/STAT signaling pathway, both of which worked synergistically in HLH treatment. As ruxolitinib has already been extensively used in clinics with favorable safety, and M@NP is biodegradable and highly biocompatible, M@NP-R has good prospects for clinical translation.

Cell Membrane-Coated Biomimetic Nanoparticles in Cancer Treatment.

Nanoparticle-based drug delivery systems hold promise for cancer treatment by enhancing the solubility and stability of anti-tumor drugs. Nonetheless, the challenges of inadequate targeting and limited biocompatibility persist. In recent years, cell membrane nano-biomimetic drug delivery systems have emerged as a focal point of research and development, due to their exceptional traits, including precise targeting, low toxicity, and good biocompatibility. This review outlines the categorization and advantages of cell membrane bionic nano-delivery systems, provides an introduction to preparation methods, and assesses their applications in cancer treatment, including chemotherapy, gene therapy, immunotherapy, photodynamic therapy, photothermal therapy, and combination therapy. Notably, the review delves into the challenges in the application of various cell membrane bionic nano-delivery systems and identifies opportunities for future advancement. Embracing cell membrane-coated biomimetic nanoparticles presents a novel and unparalleled avenue for personalized tumor therapy.

Cancer Cell Membrane-Coated Nanoparticles for Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photothermal/Photodynamic Therapy and Autophagy Inhibition

Cancer Cell Membrane-Coated Nanoparticles for Treatment of Oral Tongue Squamous Cell Carcinoma by Combining Photothermal/Photodynamic Therapy and Autophagy Inhibition

Macrophage membrane-coated Eucommia ulmoides polysaccharides-loaded PLGA nanoparticles as an effective antigen-targeted delivery system

Polysaccharides derived from Eucommia ulmoides leaves have immune-regulating, hypoglycemic, anti-tumor, and other beneficial functions. As a drug delivery system, polylactic-glycolic acid copolymer (PLGA) offers advantages like immunogenicity enhancement, improved drug absorption, and increased drug bioavailability. Currently, macrophage membranes are successfully employed in biomimetic nanomaterials to enhance drug utilization and extend drug administration time in the body, exhibiting good immunogenicity and organ targeting. In this study, we developed biomimetic PsEUL PLGA nanoparticles (NPs) coated with macrophage membrane (MM-PPsEUL) and examined their immune activity in vitro and in vivo. In vitro, MM-PPsEUL increased the phagocytic efficiency of macrophages without affecting their activity. In vivo, MM-PPsEUL significantly elevated the immune organ index of mice and upregulated the level of ovalbumin-specific IgG antibodies in serum. Simultaneously, it increased the expressions of cytokines IFN-γ and IL-4, as well as the levels of TLR4, MyD88, TRAF6, and NF-κB p65 proteins in mice spleen. MM-PPsEUL also exhibited a targeting effect on inguinal lymph nodes and slowed down the release rate of antigens, thereby inducing a prolonged immune response. In summary, MM-PPsEUL provides sustained release capabilities and can induce both humoral and cellular immune responses. This makes MM-PPsEUL NPs a promising antigen-targeted delivery system.