Biomimetic cell-derived nanocarriers in cancer research.

Nanoparticles have now long demonstrated capabilities that make them attractive to use in biology and medicine. Some of them, such as lipid nanoparticles (SARS-CoV-2 vaccines) or metallic nanoparticles (contrast agents) are already approved for their use in the clinic. However, considering the constantly growing body of different formulations and the huge research around nanomaterials the number of candidates reaching clinical trials or being commercialized is minimal. The reasons behind being related to the "synthetic" and "foreign" character of their surface. Typically, nanomaterials aiming to develop a function or deliver a cargo locally, fail by showing strong off-target accumulation and generation of adverse responses, which is connected to their strong recognition by immune phagocytes primarily. Therefore, rendering in negligible numbers of nanoparticles developing their intended function. While a wide range of coatings has been applied to avoid certain interactions with the surrounding milieu, the issues remained. Taking advantage of the natural cell membranes, in an approach that resembles a cell transfer, the use of cell-derived surfaces has risen as an alternative to artificial coatings or encapsulation methods. Biomimetic technologies are based on the use of isolated natural components to provide autologous properties to the nanoparticle or cargo being encapsulated, thus, improving their therapeutic behavior. The main goal is to replicate the (bio)-physical properties and functionalities of the source cell and tissue, not only providing a stealthy character to the core but also taking advantage of homotypic properties, that could prove relevant for targeted strategies. Such biomimetic formulations have the potential to overcome the main issues of approaches to provide specific features and identities synthetically. In this review, we provide insight into the challenges of nano-biointerfaces for drug delivery; and the main applications of biomimetic materials derived from specific cell types, focusing on the unique strengths of the fabrication of novel nanotherapeutics in cancer therapy.

Silk Fibroin-Coated Liposomes as Biomimetic Nanocarrier for Long-Term Release Delivery System in Cancer Therapy.

Despite much progress in cancer therapy, conventional chemotherapy can cause poor biodistribution and adverse side-effects on healthy cells. Currently, various strategies are being developed for an effective chemotherapy delivery system. Silk fibroin (SF) is a natural protein used in a wide range of biomedical applications including cancer therapy due to its biocompatibility, biodegradability, and unique mechanical properties. In this study, SF-coated liposomes (SF-LPs) were prepared as a biomimetic drug carrier. Physicochemical properties of SF-LPs were characterized by Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering, zeta potential measurement, and transmission electron microscopy (TEM). In vitro release of SF-LPs loaded with doxorubicin (DOX-SF-LPs) was evaluated over 21 days. Anticancer activity of DOX-SF-LPs was determined against MCF-7 and MDA-MB231 cells using the MTT assay. SF-LPs containing 1% SF exhibited favorable characteristics as a drug carrier. SF coating modified the kinetics of drug release and reduced the cytotoxic effect against L929 fibroblasts as compared to the uncoated liposomes containing cationic lipid. DOX-SF-LPs showed anticancer activity against breast cancer cells after 48 h or 72 h at 20 µM of DOX. This approach provides a potential platform of long-term release that combines biocompatible SF and phospholipids for cancer therapy, achieving efficient drug delivery and reducing side-effects.

Biomimetic Oil-in-Water Nanoemulsions as a Suitable Drug Delivery System to Target Inflamed Endothelial Cells.

Currently, the biomimetic approach of drawing inspiration from nature has frequently been employed in designing drug nanocarriers (NCs) of actively target various diseases, ranging from cancer to neuronal and inflammation pathologies. The cell-membrane coating can confer upon the inner nanomaterials a biological identity and the functions exhibited by the cells from which the membrane is derived. Monocyte- and macrophage-membrane-coated nanomaterials have emerged as an ideal delivery system to target inflamed vasculature. Herein, we developed two biomimetic NCs using a human-derived leukaemia monocytic cell line (THP-1), either undifferentiated or differentiated by phorbol 12-myristate 13-acetate (PMA) into adherent macrophage-like cells as membrane sources for NC coating. We employed a secondary oil-in-water nano-emulsion (SNE) as the inner core, which served as an optimal NC for high payloads of lipophilic compounds. Two different biomimetic systems were produced, combining the biomimetic features of biological membranes with the physicochemical and nano-sized characteristics of SNEs. These systems were named Monocyte NEsoSome (M-NEsoSome) and Macrophage NEsoSome (M0-NEsoSome). Their uptake ability was investigated in tumour necrosis factor alfa (TNFα)-treated human umbilical vein endothelial cells (HUVECs), selected as a model of inflamed endothelial cells. The M0 membrane coating demonstrated accelerated internalisation compared with the monocyte coating and notably surpassed the uptake rate of bare NCs. In conclusion, M0-NEsoSome NCs could be a therapeutic system for targeting inflamed endothelial cells and potentially delivering anti-inflammatory drugs in vascular inflammation.

Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.

Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.

Multifunctional Biomimetic Nanocarriers for Dual-Targeted Immuno-Gene Therapy Against Hepatocellular Carcinoma.

Growing evidences have proved that tumors evade recognition and attack by the immune system through immune escape mechanisms, and PDL1/Pbrm1 genes have a strong correlation with poor response or resistance to immune checkpoint blockade (ICB) therapy. Herein, a multifunctional biomimetic nanocarrier (siRNA-CaP@PD1-NVs) is developed, which can not only enhance the cytotoxic activity of immune cells by blocking PD1/PDL1 axis, but also reduce tumor immune escape via Pbrm1/PDL1 gene silencing, leading to a significant improvement in tumor immunosuppressive microenvironment. Consequently, the nanocarrier promotes DC cell maturation, enhances the infiltration and activity of CD8+ T cells, and forms long-term immune memory, which can effectively inhibit tumor growth or even eliminate tumors, and prevent tumor recurrence and metastasis. Overall, this study presents a powerful strategy for co-delivery of siRNA drugs, immune adjuvant, and immune checkpoint inhibitors, and holds great promise for improving the effectiveness and safety of current immunotherapy regimens.

Tumor Targeting with Apatinib-loaded Nanoparticles and Sonodynamic Combined Therapy

INTRODUCTION: This study implies the enhancement of apatinib killing effect in 4T1 tumor cells through constructing drug-loaded nanoparticles apatinib/Ce6@ZIF-8@Membranes (aCZM) to enhance tumor therapeutic targeting and reduce toxic side following sonodynamic therapy (SDT). METHODS: apatinib/Ce6@ZIF-8 (aCZ) were synthesized by in situ encapsulation, and aCZM were constructed by encapsulating the nanoparticles with extracted breast cancer 4T1 cell membranes. aCZM were characterized and tested for the stability by electron microscopy, and the membrane proteins on the nanoparticles' surface were assessed using SDS-PAGE gel electrophoresis. The cell viability of 4T1 cells following treatment with aCZM was tested using cell counting kit-8 (CCK-8). The uptake of nanoparticles was detected by laser confocal microscopy and flow cytometry, and the SDT-mediated production of reactive oxygen species (ROS) was verified by singlet oxygen sensor green (SOSG), electron spin resonance (ESR), and DCFH-DA fluorescent probes. The CCK-8 assay and flow cytometry using Calcein/PI were used to assess the antitumoral effect of aCZM nanoparticles under SDT. The biosafety of aCZM was further verified in vitro and in vivo using the hemolysis assay, routine blood test and H&E staining of vital organs in Balb/c mice. RESULTS: aCZM with an average particle size of about 210.26 nm were successfully synthesized. The results of the SDS-PAGE gel electrophoresis experiment showed that aCZM have a band similar to that of pure cell membrane proteins. The CCK-8 assay demonstrated the absence of effects on cell viability at a low concentration range, and the relative cell survival rate reached more than 95%. Laser confocal microscopy and flow cytometry analysis showed that aCZM treated group has the strongest fluorescence and the highest cellular uptake of nanoparticles. SOSG, ESR, and DCFH-DA fluorescent probes all indicated that the aCZM + SDT treated group has the highest ROS production. The CCK-8 assay also showed that when the ultrasound intensity was fixed at 0.5 W/cm2, the relative cell survival rates in the medium concentration group (10 µg/ml) (5.54 ± 1.26%) and the high concentration group (20 µg/ml) (2.14 ± 1.63%) were significantly lower than those in the low concentration group (5 µg/ml) (53.40 ± 4.25%). Moreover, there was a concentration and intensity dependence associated with the cell-killing effect. The mortality rate of the aCZM in the ultrasound group (44.95±3.03%) was significantly higher than that of the non-ultrasound (17.00±2.26%) group and aCZ + SDT group (24.85 ± 3.08%) (P<0.0001). The live and dead cells' staining (Calcein/PI) also supported this result. Finally, in vitro hemolysis test at 4 and 24 hours showed that the hemolysis rate of the highest concentration group was less than 1%. The blood routine, biochemistry, and H&E staining results of major organs in Balb/c mice undergoing nano-treatments showed no obvious functional abnormalities and tissue damage in 30 days. CONCLUSION: In this study, a multifunctional bionic drug delivery nanoparticles (aCZM) system with good biosafety and compatibility in response to acoustic dynamics was successfully constructed and characterized. This system enhanced apatinib killing effect on tumor cells and reduced toxic side effects under SDT.

Antiviral Nanobiologic Therapy Remodulates Innate Immune Responses to Highly Pathogenic Coronavirus.

Highly pathogenic coronavirus (CoV) infection induces a defective innate antiviral immune response coupled with the dysregulated release of proinflammatory cytokines and finally results in acute respiratory distress syndrome (ARDS). A timely and appropriate triggering of innate antiviral response is crucial to inhibit viral replication and prevent ARDS. However, current medical countermeasures can rarely meet this urgent demand. Here, an antiviral nanobiologic named CoVR-MV is developed, which is polymerized of CoVs receptors based on a biomimetic membrane vesicle system. The designed CoVR-MV interferes with the viral infection by absorbing the viruses with maximized viral spike target interface, and mediates the clearance of the virus through its inherent interaction with macrophages. Furthermore, CoVR-MV coupled with the virus promotes a swift production and signaling of endogenous type I interferon via deregulating 7-dehydrocholesterol reductase (DHCR7) inhibition of interferon regulatory factor 3 (IRF3) activation in macrophages. These sequential processes re-modulate the innate immune responses to the virus, trigger spontaneous innate antiviral defenses, and rescue infected Syrian hamsters from ARDS caused by SARS-CoV-2 and all tested variants.

Biomimetic Redox-Responsive Mesoporous Organosilica Nanoparticles Enhance Cisplatin-Based Chemotherapy.

Cisplatin-based chemotherapy is dominated in several cancers; however, insufficient therapeutic outcomes and systemic toxicity hamper their clinical applications. Controlled release of cisplatin and reducing inactivation remains an urgent challenge to overcome. Herein, diselenide-bridged mesoporous organosilica nanoparticles (MON) coated with biomimetic cancer cell membrane were tailored for coordination responsive controlled cisplatin delivery and GSH depletion to strengthen Pt-based chemotherapy. Cisplatin-loaded MON (MON-Pt) showed high loading capacity due to robust coordination between selenium and platinum atoms and preventing premature leakage in normal tissue. MON-Pt exhibited a controlled release of activated cisplatin in response to the redox tumor microenvironment. Meanwhile, MON-Pt containing redox-responsive diselenide bonds could efficiently scavenge intracellular inactivation agents, such as GSH, to enhance Pt-based chemotherapy. 4T1 breast cancer cell membranes cloaked MON-Pt (MON-Pt@CM) performed efficient anticancer performance and low in vivo system toxicity due to long blood circulation time and high tumor accumulation benefiting from the tumor targeting and immune-invasion properties of the homologic cancer cell membrane. These results suggest a biomimetic nanocarrier to control release and reduce the inactivation of cisplatin for efficient and safe Pt-based chemotherapy by responding and regulating the tumor microenvironment.

Cell membrane-coated nanosized active targeted drug delivery systems homing to tumor cells: A review.

Cancer is a leading cause of mortality worldwide. Cell membrane-coated nanocarriers actively targeting tumor sites are known to circumvent the limitations of conventional treatments and nanosized drug delivery systems. Cell membrane-coated nanocarriers can evade the immune system and can target tumors, thereby exhibiting a prolonged circulation time, enhancing tumor accumulation, increasing cancer therapeutic efficacy, and facilitating tumor imaging in vivo. Numerous studies have focused on cell membrane-coated nanocarriers homing to tumors. The use of these biomimetic nanocarriers in combination with photothermal or photodynamic cancer therapy have received increasing attention. This review discusses various sources of cell membranes, which have been harnessed previously in this field and highlights the mechanism underlying the targeting action of these nanocarriers and the method of their extraction, along with the applications of biomimetic cell membrane-coated nanocarriers in cancer phototherapy and diagnosis. Finally, this review discusses prospects in methods to resist cancer metastasis.

Ligand-Modified Cell Membrane Enables the Targeted Delivery of Drug Nanocrystals to Glioma.

The safe and efficient delivery of chemotherapeutic agents remains critical to anticancer therapy. Herein, we report on a targeted drug delivery system based upon a modified cell membrane coating technique and drug nanocrystals (NCs). Specifically, red blood cell (RBC) membrane was modified with targeting peptides through a facile insertion method involving avidin-biotin interactions. The RBC membrane-coated drug NCs (RBC-NCs) exhibited high drug loading, long-term stability, excellent biocompatibility, and prolonged retention time, all of which make them suitable for effective drug delivery. When modified with the tumor-targeting peptide c(RGDyK), the resulting RGD-RBC-NCs showed superior tumor accumulation and therapeutic efficacy both in mice bearing a subcutaneous tumor as well as orthotropic glioma. RBC-NC therapeutics can be readily generalized to the delivery of various drugs and for the treatment of a wide range of cancers.

Reconstituted high-density lipoproteins: novel biomimetic nanocarriers for drug delivery.

High-density lipoproteins (HDL) are naturally-occurring nanoparticles that are biocompatible, non-immunogenic and completely biodegradable. These endogenous particles can circulate for an extended period of time and transport lipids, proteins and microRNA from donor cells to recipient cells. Based on their intrinsic targeting properties, HDL are regarded as promising drug delivery systems. In order to produce on a large scale and to avoid blood borne pollution, reconstituted high-density lipoproteins (rHDL) possessing the biological properties of HDL have been developed. This review summarizes the biological properties and biomedical applications of rHDL as drug delivery platforms. It focuses on the emerging approaches that have been developed for the generation of biomimetic nanoparticles rHDL to overcome the biological barriers to drug delivery, aiming to provide an alternative, promising avenue for efficient targeting transport of nanomedicine.

Anti-EGFR-iRGD recombinant protein modified biomimetic nanoparticles loaded with gambogic acid to enhance targeting and antitumor ability in colorectal cancer treatment.

BACKGROUND: Red blood cell membrane-coated nanoparticle (RBCm-NP) platform, which consist of natural RBCm and synthetic polymeric core, can extend circulation time in vivo with an improved biocompatibility and stability of this biomimetic nanocarrier. To achieve better bioavailability of antitumor drugs that were loaded in RBCm-NPs, the functionalization of coated RBCm with specific targeting ability is essential. Bispecific recombinant protein anti-EGFR-iRGD, containing both tumor penetrating peptide (internalizing RGD peptide) and EGFR single-domain antibody (sdAb), seems to be an optimal targeting ligand for RBCm-NPs in the treatment of multiple tumors, especially colorectal cancer with high EGFR expression. MATERIALS AND METHODS: We modified the anti-EGFR-iRGD recombinant protein on the surface of RBCm-NPs by lipid insertion method to construct iE-RBCm-PLGA NPs and confirmed the presentation of active tumor-targeting ability in colorectal cancer models with high EGFR expression when compared with RBCm-PLGA NPs. In addition, potential anti-tumor drug gambogic acid (GA) was loaded into the NPs to endow the antitumor efficiency of iE-RBCm-GA/PLGA NPs. It was simultaneously evaluated whether GA can reach better biocompatibility benefiting from the improved antitumor efficiency of iE-RBCm-GA/PLGA NPs in colorectal cancer models. RESULTS: We successfully modified anti-EGFR-iRGD proteins on the surface of biomimetic NPs with integrated and stable "shell-core" structure. iE-RBCm-PLGA NPs showed its improved targeting ability in vitro (multicellular spheroids [MCS]) and in vivo (nude mice bearing tumors). Besides, no matter on short-term cell apoptosis at tumor site (terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]) and long-term tumor inhibition, iE-RBCm-GA/PLGA NPs achieved better antitumor efficacy than free GA in spite of the similar effects of cytotoxicity and apoptosis to GA in vitro. CONCLUSION: We expect that the bispecific biomimetic nanocarrier can extend the clinical application of many other potential antitumor drugs similar to GA and become a novel drug carrier in the colorectal cancer treatment.