TME-Related Biomimetic Strategies Against Cancer.

The tumor microenvironment (TME) plays an important role in various stages of tumor generation, metastasis, and evasion of immune monitoring and treatment. TME targeted therapy is based on TME components, related pathways or active molecules as therapeutic targets. Therefore, TME targeted therapy based on environmental differences between TME and normal cells has been widely studied. Biomimetic nanocarriers with low clearance, low immunogenicity, and high targeting have enormous potential in tumor treatment. This review introduces the composition and characteristics of TME, including cancer­associated fibroblasts (CAFs), extracellular matrix (ECM), tumor blood vessels, non-tumor cells, and the latest research progress of biomimetic nanoparticles (NPs) based on TME. It also discusses the opportunities and challenges of clinical transformation of biomimetic nanoparticles.

Biomimetic Grapefruit-Derived Extracellular Vesicles for Safe and Targeted Delivery of Sodium Thiosulfate against Vascular Calcification.

As the prevalence of vascular calcification (VC), a strong contributor to cardiovascular morbidity and mortality, continues to increase, the need for pharmacologic therapies becomes urgent. Sodium thiosulfate (STS) is a clinically approved drug for therapy against VC; however, its efficacy is hampered by poor bioavailability and severe adverse effects. Plant-derived extracellular vesicles have provided options for VC treatment since they can be used as biomimetic drug carriers with higher biosafety and targeting abilities than artificial carriers. Inspired by natural grapefruit-derived extracellular vesicles (EVs), we fabricated a biomimetic nanocarrier comprising EVs loaded with STS and further modified with hydroxyapatite crystal binding peptide (ESTP) for VC-targeted delivery of STS. In vitro, the ESTP nanodrug exhibited excellent cellular uptake capacity by calcified vascular smooth muscle cells (VSMCs) and subsequently inhibited VSMCs calcification. In the VC mice model, the ESTP nanodrug showed preferentially the highest accumulation in the calcified arteries compared to other treatment groups. Mechanistically, the ESTP nanodrug significantly prevented VC via driving M2 macrophage polarization, reducing inflammation, and suppressing bone-vascular axis as demonstrated by inhibiting osteogenic phenotype trans-differentiation of VSMCs while enhancing bone quality. In addition, the ESTP nanodrug did not induce hemolysis or cause any damage to other organs. These results suggest that the ESTP nanodrug can prove to be a promising agent against VC without the concern of systemic toxicity.

Bioinspired yeast-based ß-glucan system for oral drug delivery.

Oral drug delivery is the preferred route of drug administration for patients, especially those who need long-term medication. Recently, bioinspired drug delivery systems have emerged for the oral delivery of various therapeutics. Among them, the yeast-based ß-glucan system is a novel and promising platform, for oral administration that can overcome the biological barriers of the harsh gastrointestinal environment. Remarkably, the yeast-based ß-glucan system not only protects the drug through the harsh gastrointestinal environment but also achieves targeted therapeutic effects by specifically recognizing immune cells, especially macrophages. Otherwise, it exhibits immunomodulatory properties. Based on the pleasant characteristics of the yeast-based ß-glucan system, they are widely used in various macrophage-related diseases for oral administration. In this review, we introduced the structure and function of yeast-based ß-glucan. Subsequently, we further summarized the current preparation methods of yeast-based ß-glucan carriers and the strategies for preparing yeast-based ß-glucan drug delivery systems. In addition, we focus on discussing the applications of ß-glucan drug delivery systems in various diseases. Finally, the current challenges and future perspectives of the ß-glucan drug delivery system are introduced.

Neutrophil membrane biomimetic delivery system (Ptdser-NM-Lipo/Fer-1) designed for targeting atherosclerosis therapy.

Atherosclerosis is a progressive inflammatory disease characterised by excessive lipid accumulation and inflammatory cell infiltration and is the basis of most cardiovascular diseases and peripheral arterial diseases. Therefore, an effectively targeted delivery system is urgently needed to deliver ferroptosis-specific inhibitors to the site of arterial plaque and the inflammatory microenvironment. Inspired by the fact that neutrophils can be recruited to arterial plaques under the action of adhesion molecules and chemokines, the authors developed a neutrophil membrane hybrid liposome nano-mimetic system (Ptdser-NM-Lipo/Fer-1) that delivers Ferrostatin-1 (Fer-1) to the atherosclerotic plaque effectively, which is composed of Fer-1-loaded Ptdser-modified liposomes core and neutrophils shell. Fer-1 was released at the AS plaque site to remove reactive oxygen species (ROS) and improve the inflammatory microenvironment. In vitro ROS clearance experiments have shown that 50 µmol/ml Fer-1 can significantly remove ROS produced by H2 O2 -induced MOVAS cells and Ptdser-NM-Lipo/Fer-1 revealed a 3-fold increase in the inhibition rate of ROS than free Fer-1 in induced-RAW264.7, demonstrating its superior ROS-cleaning effect. Based on the interaction of adhesion molecules, such as vascular cell adhesion molecule 1, ICAM-1, P-selectin, E-selectin, and chemokines released in the inflamed site, the aorta in NM-Lipo-treated mice displayed 1.3-fold greater radiant efficiency than platelet membrane-Lipo-treated mice. Meanwhile, due to the modification of the Ptdser, the aorta in Ptdser-NM-Lipo/Fer-1-treated mice exhibited the highest fluorescence intensity, demonstrating its excellent targeting ability for atherosclerosis. Therefore, we present a specific formulation for the treatment of atherosclerosis with the potential for novel therapeutic uses.

Application of biomimetic nano drug delivery system of macrophage membrane in disease targeted therapy / 中国药房

In recent years ，biomimetic nanodelivery system based on cell membrane coating has developed rapidly and shows better biocompatibility and efficacy than traditional nanodelivery systems in a variety of diseases . Macrophages，as members of the immune system ，are closely related to the occurrence and development of a variety of diseases . Macrophages are derived from monocytes and can be polarized into M 1 and M 2 types after corresponding stimulation ： M1 macrophages involved in the proinflammatory reaction and M 2 macrophages involved in the inflammatory reaction . This paper reviews the application status of biomimetic nanoparticles coated with macrophage membrane in disease targeted therapy in recent years . Biomimetic nanoparticles coated with macrophage membrane has shown its high targeting and low immunogenicity in the treatment of malignant tumors （breast cancer ，colorectal cancer ，melanoma，glioma），Alzheimer’s disease ，liver ischemia -reperfusion injury ，atherosclerosis and so on . However，the research of Biomimetic nanoparticles coated with macrophage membrane currently focuses on anti -tumor research and is still in the laboratory research stage .

A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

A novel macrophage-mediated biomimetic delivery system with NIR-triggered release for prostate cancer therapy.

BACKGROUND: Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. RESULTS: At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. CONCLUSIONS: The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.

Macrophage-Membrane-Coated Nanoparticles for Tumor-Targeted Chemotherapy.

Various delivery vectors have been integrated within biologically derived membrane systems to extend their residential time and reduce their reticuloendothelial system (RES) clearance during systemic circulation. However, rational design is still needed to further improve the in situ penetration efficiency of chemo-drug-loaded membrane delivery-system formulations and their release profiles at the tumor site. Here, a macrophage-membrane-coated nanoparticle is developed for tumor-targeted chemotherapy delivery with a controlled release profile in response to tumor microenvironment stimuli. Upon fulfilling its mission of tumor homing and RES evasion, the macrophage-membrane coating can be shed via morphological changes driven by extracellular microenvironment stimuli. The nanoparticles discharged from the outer membrane coating show penetration efficiency enhanced by their size advantage and surface modifications. After internalization by the tumor cells, the loaded drug is quickly released from the nanoparticles in response to the endosome pH. The designed macrophage-membrane-coated nanoparticle (cskc-PPiP/PTX@Ma) exhibits an enhanced therapeutic effect inherited from both membrane-derived tumor homing and step-by-step controlled drug release. Thus, the combination of a biomimetic cell membrane and a cascade-responsive polymeric nanoparticle embodies an effective drug delivery system tailored to the tumor microenvironment.

Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer.

The biomimetic delivery system (BDS) based on special types of endogenous cells like macrophages and T cells, has been emerging as a novel strategy for cancer therapy, due to its tumor homing property and biocompatibility. However, its development is impeded by complicated construction, low drug loading or negative effect on the cell bioactivity. The present report constructed a BDS by loading doxorubicin (DOX) into a mouse macrophage-like cell line (RAW264.7). It was found that therapeutically meaningful amount of DOX could be loaded into the RAW264.7 cells by simply incubation, without significantly affecting the viability of the cells. Drug could release from the BDS and maintain its activity. RAW264.7 cells exhibited obvious tumor-tropic capacity towards 4T1 mouse breast cancer cells both in vitro and in vivo, and drug loading did not alter this tendency. Importantly, the DOX loaded macrophage system showed promising anti-cancer efficacy in terms of tumor suppression, life span prolongation and metastasis inhibition, with reduced toxicity. In conclusion, it is demonstrated that the BDS developed here seems to overcome some of the main issues related to a BDS. The DOX loaded macrophages might be a potential BDS for targeted cancer therapy.