Near Infrared-Activatable Biomimetic Nanoplatform for Tumor-Specific Drug Release, Penetration and Chemo-Photothermal Synergistic Therapy of Orthotopic Glioblastoma.

Introduction: Glioblastoma multiforme (GBM), a highly invasive and prognostically challenging brain cancer, poses a significant hurdle for current treatments due to the existence of the blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Methods: We present a biomimetic nanoplatform with angiopep-2-modified macrophage membrane, loaded with indocyanine green (ICG) templated self-assembly of SN38 (AM-NP), facilitating active tumor targeting and effective blood-brain barrier penetration through specific ligand-receptor interaction. Results: Upon accumulation at tumor sites, these nanoparticles achieved high drug concentrations. Subsequent combination of laser irradiation and release of chemotherapy agent SN38 induced a synergistic chemo-photothermal therapy. Compared to bare nanoparticles (NPs) lacking cell membrane encapsulation, AM-NPs significantly suppressed tumor growth, markedly enhanced survival rates, and exhibited excellent biocompatibility with minimal side effects. Conclusion: This NIR-activatable biomimetic camouflaging macrophage membrane-based nanoparticles enhanced drug delivery targeting ability through modifications of macrophage membranes and specific ligands. It simultaneously achieved synergistic chemo-photothermal therapy, enhancing treatment effectiveness. Compared to traditional treatment modalities, it provided a precise, efficient, and synergistic method that might have contributed to advancements in glioblastoma therapy.

Targeted Delivery of Macrophage Membrane Biomimetic Liposomes Through Intranasal Administration for Treatment of Ischemic Stroke.

Purpose: Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration. Methods: MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated. Results: Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life. Conclusion: MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.

Macrophage membrane camouflaged reactive oxygen species responsive nanomedicine for efficiently inhibiting the vascular intimal hyperplasia.

BACKGROUND: Intimal hyperplasia caused by vascular injury is an important pathological process of many vascular diseases, especially occlusive vascular disease. In recent years, Nano-drug delivery system has attracted a wide attention as a novel treatment strategy, but there are still some challenges such as high clearance rate and insufficient targeting. RESULTS: In this study, we report a biomimetic ROS-responsive MM@PCM/RAP nanoparticle coated with macrophage membrane. The macrophage membrane with the innate "homing" capacity can superiorly regulate the recruitment of MM@PCM/RAP to inflammatory lesion to enhance target efficacy, and can also disguise MM@PCM/RAP nanoparticle as the autologous cell to avoid clearance by the immune system. In addition, MM@PCM/RAP can effectively improve the solubility of rapamycin and respond to the high concentration level of ROS accumulated in pathological lesion for controlling local cargo release, thereby increasing drug availability and reducing toxic side effects. CONCLUSIONS: Our findings validate that the rational design, biomimetic nanoparticles MM@PCM/RAP, can effectively inhibit the pathological process of intimal injury with excellent biocompatibility.

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

BACKGROUND: Biomimetic 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. RESULTS: Herein, 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. CONCLUSIONS: TME-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.

Higher Order Protein Catenation Leads to an Artificial Antibody with Enhanced Affinity and In Vivo Stability.

The chemical topology is a unique dimension for protein engineering, yet the topological diversity and architectural complexity of proteins remain largely untapped. Herein, we report the biosynthesis of complex topological proteins using a rationally engineered, cross-entwining peptide heterodimer motif derived from p53dim (an entangled homodimeric mutant of the tetramerization domain of the tumor suppressor protein p53). The incorporation of an electrostatic interaction at specific sites converts the p53dim homodimer motif into a pair of heterodimer motifs with high specificity for directing chain entanglement upon folding. Its combination with split-intein-mediated ligation and/or SpyTag/SpyCatcher chemistry facilitates the programmed synthesis of protein heterocatenane or [n]catenanes in cells, leading to a general and modular approach to complex protein catenanes containing various proteins of interest. Concatenation enhances not only the target protein's affinity but also the in vivo stability as shown by its prolonged circulation time in blood. As a proof of concept, artificial antibodies have been developed by embedding a human epidermal growth factor receptor 2-specific affibody onto the [n]catenane scaffolds and shown to exhibit a higher affinity and a better pharmacokinetic profile than the wild-type affibody. These results suggest that topology engineering holds great promise in the development of therapeutic proteins.

Cell-derived biomimetic nanocarriers for targeted cancer therapy: cell membranes and extracellular vesicles.

Nanotechnology provides synthetic carriers for cancer drug delivery that protect cargos from degradation, control drug release and increase local accumulation at tumors. However, these non-natural vehicles display poor tumor targeting and potential toxicity and are eliminated by the immune system. Recently, biomimetic nanocarriers have been widely developed based on the concept of 'mimicking nature.' Among them, cell-derived biomimetic vehicles have become the focus of bionics research because of their multiple natural functions, such as low immunogenicity, long circulation time and targeting ability. Cell membrane-coated carriers and extracellular vesicles are two widely used cell-based biomimetic materials. Here, this review summarizes the latest progress in the application of these two biomimetic carriers in targeted cancer therapy. Their properties and performance are compared, and their future challenges and development prospects are discussed.

Harnessing the nano-bio interface: Application of membrane coating to long acting silica particles.

Interaction of conventional drug delivery systems such as polymeric or lipid based nano- and microparticles with the in vivo milieu has garnered significant interest, primarily to orchestrate immune escape and/or improve targeting. Surface modification with targeting ligands has been heavily relied upon for the mentioned purpose in the recent years. However, the surface modified particles can also activate the immune system. Large-scale manufacturing can also be a challenge, as surface modification needs to be reproducible. Furthermore, in vivo, the targeting is dependent on the receptor expression density and number of target sites, which adds to the pharmacokinetic variability of the constructs. An evolving paradigm to overcome complications of surface functionalization is the incorporation of bio-inspired topographies into these conventional delivery systems to enable them to better interact with biological systems. Biomimetic delivery systems combine the unique surface composition of cells or cell membranes, and versatility of synthetic nanoparticles. In this review, we focus on one such delivery system, silica particles, and explore their interaction with different biological membranes.

Hemoglobin-mediated biomimetic synthesis of paramagnetic O2-evolving theranostic nanoprobes for MR imaging-guided enhanced photodynamic therapy of tumor.

The hypoxic microenvironment in solid tumors severely limits the efficacy of photodynamic therapy (PDT). Therefore, the development of nanocarriers co-loaded with photosensitizers and oxygen, together with imaging guidance ability, is of great significance in cancer therapy. However, previously reported synthetic methods for these multi-functional probes are complicated, and the raw materials used are toxic. Methods: Herein, the human endogenous protein, hemoglobin (Hb), was used for the simultaneous biomimetic synthesis of Gd-based nanostructures and co-loading of Chlorine e6 (Ce6) and oxygen for alleviating the hypoxic environment of tumors and accomplishing magnetic resonance imaging (MRI)-guided enhanced PDT. The Gd@HbCe6-PEG nanoprobes were synthesized via a green and protein biomimetic approach. The physicochemical properties, including relaxivity, oxygen-carrying/release capability, and PDT efficacy of Gd@HbCe6-PEG, were measured in vitro and in vivo on tumor-bearing mice after intravenous injection. Morphologic and functional MRI were carried out to evaluate the efficacy of PDT. Results: The results demonstrated the successful synthesis of compact Gd@HbCe6-PEG nanostructures with desired multi-functionalities. Following treatment with the nanoparticles, the embedded MR moiety was effective in lighting tumor lesions and guiding therapy. The oxygen-carrying capability of Hb after biomimetic synthesis was confirmed by spectroscopic analysis and oxygen detector in vitro. Further, tumor oxygenation for alleviating tumor hypoxia in vivo after intravenous injection of Gd@HbCe6-PEG was verified by photoacoustic imaging and immunofluorescence staining. The potent treatment efficacy of PDT on early-stage was observed by the morphologic and functional MR imaging. Importantly, rapid renal clearance of the particles was observed after treatment. Conclusion: In this study, by using a human endogenous protein, we demonstrated the biomimetic synthesis of multi-functional nanoprobes for simultaneous tumor oxygenation and imaging-guided enhanced PDT. The therapeutic efficacy could be quantitatively confirmed at 6 h post PDT with diffusion-weighted imaging (DWI).

Marine biomaterials: Biomimetic and pharmacological potential of cultivated Aplysina aerophoba marine demosponge.

Marine demosponges of the Verongiida order are considered a gold-mine for bioinspired materials science and marine pharmacology. The aim of this work was to simultaneously isolate selected bromotyrosines and unique chitinous structures from A. aerophoba and to propose these molecules and biomaterials for possible application as antibacterial and antitumor compounds and as ready-to-use scaffolds for cultivation of cardiomyocytes, respectively. Among the extracted bromotyrosines, the attention has been focused on aeroplysinin-1 that showed interesting unexpected growth inhibition properties for some Gram-negative clinical multi-resistant bacterial strains, such as A. baumannii and K. pneumoniae, and on aeroplysinin-1 and on isofistularin-3 for their anti-tumorigenic activity. For both compounds, the effects are cell line dependent, with significant growth inhibition activity on the neuroblastoma cell line SH-SY5Y by aeroplysinin-1 and on breast cancer cell line MCF-7 by isofistularin-3. In this study, we also compared the cultivation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) on the A. aerophoba chitinous scaffolds, in comparison to chitin structures that were pre-coated with Geltrex™, an extracellular matrix mimetic which is used to enhance iPSC-CM adhesion. The iPSC-CMs on uncoated and pure chitin structures started contracting 24 h after seeding, with comparable behaviour observed on Geltrex-coated cell culture plates, confirming the biocompatibility of the sponge biomaterial with this cell type. The advantage of A. aerophoba is that this source organism does not need to be collected in large quantities to supply the necessary amount for further pre-clinical studies before chemical synthesis of the active compounds will be available. A preliminary analysis of marine sponge bioeconomy as a perspective direction for application of biomaterials and secondary bioactive metabolites has been finally performed for the first time.

Chemotaxis-driven delivery of nano-pathogenoids for complete eradication of tumors post-phototherapy.

The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery.

Charge Conversional Biomimetic Nanocomplexes as a Multifunctional Platform for Boosting Orthotopic Glioblastoma RNAi Therapy.

Nanotechnology-based RNA interference (RNAi) has shown great promise in overcoming the limitations of traditional clinical treatments for glioblastoma (GBM). However, because of the complexity of brain physiology, simple blood-brain barrier (BBB) penetration or tumor-targeting strategies cannot entirely meet the demanding requirements of different therapeutic delivery stages. Herein, we developed a charge conversional biomimetic nanoplatform with a three-layer core-shell structure to programmatically overcome persistent obstacles in siRNA delivery to GBM. The resulting nanocomplex presents good biocompatibility, prolonged blood circulation, high BBB transcytosis, effective tumor accumulation, and specific uptake by tumor cells in the brain. Moreover, red blood cell membrane (RBCm) disruption and effective siRNA release can be further triggered elegantly by charge conversion from negative to positive in the endo/lysosome (pH 5.0-6.5) of tumor cells, leading to highly potent target-gene silencing with a strong anti-GBM effect. Our study provides an intelligent biomimetic nanoplatform tailored for systemically siRNA delivery to GBM, leveraging Angiopep-2 peptide-modified, immune-free RBCm and charge conversional components. Improved therapeutic efficacy, higher survival rates, and minimized systemic side effects were achieved in orthotopic U87MG-luc human glioblastoma tumor-bearing nude mice.

Eliciting an immune hot tumor niche with biomimetic drug-based multi-functional nanohybrids augments immune checkpoint blockade-based breast cancer therapy.

Immune checkpoint blockade (ICB) has emerged as one of the breakthrough approaches for tumor immunotherapy. However, known as an immune "cold" tumor, breast cancer harbors an immunosuppressive tumor niche that compromises ICB-based therapy. Chemoimmunotherapy combines a chemotherapeutic with an immune-modulating agent, representing a promising tactic to combat cancers, while the lack of effectively targeted co-delivery strategy is one of the main obstacles to achieve the synergistic utilization. Herein, self-assembled PEGylated pure drug-based nanohybrids (DNH) were created, which could evoke immunogenic cell death (ICD), aiding ICB-based immunotherapy by controlling the spatiotemporal release of oxaliplatin (OXA) and small molecular inhibitor 1-methyl-d-tryptophan (1-MT). Furthermore, biomimetic functionalization was exploited by nature killer cell membrane camouflaging to target cancerous cells as well as by elicit immune response through inducing M1 macrophage polarization. The drug release profiles of the nanosystem were investigated in the presence of low pH and intracellular reductants. Systemic in vivo bio-behaviors were evaluated via pharmacokinetics and biodistribution. As an "all-in-one" pure drug-based codelivery system, our biomimetic nanoplatform possessed multiple immunomodulation functions, which markedly aided in increasing the frequency of immune responders and generate an immune "hot" breast tumor niche, and eventually allowed to boost breast cancer therapy.

Anisotropic poly(lactic-co-glycolic acid) microparticles enable sustained release of a peptide for long-term inhibition of ocular neovascularization.

Leading causes of vision loss include neovascular age-related macular degeneration (NVAMD) and macular edema (ME), which both require frequent intravitreal injections for treatment. A safe, poly(lactic-co-glycolic acid) (PLGA)-based biodegradable polymeric microparticle (MP) delivery system was developed that encapsulates and protects a biomimetic peptide from degradation, allows sustained intraocular release through polymer hydrolysis, and demonstrates a prolonged anti-angiogenic effect in vivo in three different NVAMD animal models (a laser-induced choroidal neovascularization mouse model, a rhoVEGF transgenic mouse model, and a Tet/opsin/VEGF transgenic mouse model) following intravitreal administration. The role of copolymer composition and microparticle shape was explored and 85:15 lactide-to-glycolide PLGA formed into ellipsoidal microparticles was found to be effective at inhibiting neovascularization for at least 16 weeks in vivo. Treatments were found to not only inhibit the growth of neovascularization, but also to cause regression of the neovasculature, reduce vascular leakage, and prevent exudative retinal detachment. These particulate devices are promising for the sustained release of biologics in the eye and may be useful for treating retinal diseases. STATEMENT OF SIGNIFICANCE: Devastating retinal diseases cause blindness in millions of people around the world. Current protein-based treatments have insufficient efficacy for many patients and also necessitate frequent intravitreal injections. Here, we demonstrate a new treatment consisting of a peptide encapsulated in biodegradable microparticles. We explore the effects of copolymer composition and physical shape of polymeric microparticles and find that both modulate peptide release. Efficacy of the treatment was validated in three different mouse models and the lead formulation was determined to be effective long-term, for at least 16 weeks in vivo, following a single injection. Treatments inhibited and regressed neovascularization as well as reduced vascular leakage. Anisotropic polymeric microparticles are promising for the sustained release of biologics in the eye.

Size Dependency of Circulation and Biodistribution of Biomimetic Nanoparticles: Red Blood Cell Membrane-Coated Nanoparticles.

Recently, biomimetic nanoparticles, especially cell membrane-cloaked nanoparticles, have attracted increasing attention in biomedical applications, including antitumor therapy, detoxification, and immune modulation, by imitating the structure and the function of biological systems such as long circulation life in the blood. However, the circulation time of cell membrane-cloaked nanoparticles is far less than that of the original cells, greatly limiting their biomedical applications, while the underlying reasons are seldom demonstrated. In this study, the influence of particle size on the circulation and the biodistribution of red blood cell membrane-coated nanoparticles (RBC-NPs) as model biomimetic nanoparticles were investigated. Differently sized RBC-NPs (80, 120, 160, and 200 nm) were prepared by fusing RBC membranes on poly(lactic-co-glycolic acid) nanoparticles. It was shown that the particle size did not change the cellular uptake of these biomimetic nanoparticles by macrophage cells in vitro and their immunogenic responses in vivo. However, their circulation life in vivo decreased with the particle size, while their accumulation in the liver increased with the particle size, which might be related to their size-dependent filtration through hepatic sinusoids. These findings will provide experimental evidence for the design and the optimization of biomimetic nanoparticles.

Biomimetic Pulsating Vesicles with Both pH-Tunable Membrane Permeability and Light-Triggered Disassembly-Re-assembly Behaviors Prepared by Supra-Amphiphilic Helices.

The reversible unfolding-refolding transition is considerably important for natural elastomeric proteins (e.g., titin) to fulfill their biological functions. It is of great importance to develop synthetic versions by borrowing their unique stretchable design principles. Herein, we present a novel pulsating vesicle by means of the aqueous self-assembly of supra-amphiphilic helices. Interestingly, this vesicle simultaneously features dynamic swelling and shrinkage movements in response to external proton triggers. Titin-like unfolding-refolding transformation of artificial helices was proved to play a crucial role in this pulsatile motion. Moreover, the vesicular membrane of this vesicle has exhibited tunable permeability during reversible expansion and contraction circulation. Meanwhile, light can also be used as a driving force to further regulate the disassembly-reassembly transformation of the pulsating vesicle. In addition, the drug delivery system was also employed as an investigating model to estimate the permeability variation and disassembly-reassembly behaviors of the pulsating vesicles, which displayed unique dual quick- and sustained-release behaviors toward anti-cancer agents. It is anticipated that this work opens an avenue for fabricating novel stretchable biomimetics by using the exclusive unfolding-refolding nature of artificial foldamers.

Fe-N-C Artificial Enzyme: Activation of Oxygen for Dehydrogenation and Monoxygenation of Organic Substrates under Mild Condition and Cancer Therapeutic Application.

Developing highly efficient biomimetic catalysts that directly use O2 as the terminal oxidant to dehydrogenate and monoxygenate substrates with high selectivity under mild conditions has long been pursued but rarely achieved yet. Herein, we report that heterogeneous Fe-N-C, which is commonly used as an electrocatalyst for oxygen reduction reaction, had unusual biomimetic catalytic activity in both dehydrogenation and monoxygenation of a series of organic molecules (∼100% selectivity) by directly using O2. The Fe-N x center was verified to be the active site that reductively activated O2 by spontaneously generating specific reactive oxygen species (ROS) (1O2, O2•-, and H2O2). Aided by these ROS, under physiological conditions, the Fe-N-C was further successfully exampled to kill proliferative lung cancer cells. Fe-N-C had several striking superior features with respect to natural enzymes, classical heterogeneous nanozymes, and homogeneous artificial enzymes incapable of working under harsh conditions (extreme pH and high temperature), ease of separation and recycling, and direct use of O2. It would open up a new vista of Fe-N-C as an artificial enzyme in biomimetic catalysis, ranging from fundamental simulation of oxidase/oxygenase metabolism to industrial oxidation processes and to disease treatment.

Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultrahigh Paclitaxel Payloads for Specific and Robust Chemotherapy.

Poor loading capacity and nonspecific tumor accumulation of current drug delivery system remain the critical challenges that prevent nanomedicine from maximizing therapeutic efficacy in cancer treatment. Herein, poly(ester amide) polymers composed of cationic and hydrophobic segments were formulated with a paclitaxel/human serum albumin (PTX/HSA) complex, as well as free PTX, to construct a core-shell nanoparticle (NP) platform with the interior simultaneously reserving PTX and PTX/HSA complex, while the exterior absorbing the PTX/HSA complex. Following systematic screening, the optimized NPs, namely, APP1i@e NPs, exhibited small particle size (43.95 nm), maximal PTX loading (42.23%), excellent dynamic stability (at least 1 week), and acid-triggered release. In vitro results showed that after being trafficked through caveolae-mediated endocytosis, APP1i@e NPs successfully escaped from endo-/lysosomes and then rapidly released cargos in the acidic cytosol, which continued to enhance cytotoxicity by mitochondrial control of apoptosis and suppression of microtubule dynamics. Longer circulation time and superior targeting efficiency post-intravenous injection confirmed that surface PEGylation imparted APP1i@e NPs with the ability to control their pharmacokinetics and biodistribution. The biomimetic shell design with HSA, which enlarged PTX stock and improved biosafety, made APP1i@e NPs more suitable for in vivo applications. Furthermore, in vivo safety and efficacy demonstrated that APP1i@e NPs effectively inhibited the growth of ovarian xenograft tumors, whereas significantly avoiding toxic issues associated with PTX. APP1i@e NPs with surface PEG coating and biomimetic HSA design, therefore, may provide a remarkable improvement in the therapeutic index of taxanes used in the clinic.

Surface Functionalization of Polymeric Nanoparticles with Umbilical Cord-Derived Mesenchymal Stem Cell Membrane for Tumor-Targeted Therapy.

Multiple cell plasma membranes have been utilized for surface functionalization of synthetic nanomaterials and construction of biomimetic drug delivery systems for cancer treatment. The natural characters and facile isolation of original cells facilitate the biomedical applications of plasma membranes in functionalizing nanocarriers. Human umbilical cord-derived mesenchymal stem cells (MSCs) have been identified to show tropism toward malignant lesions and have great advantages in ease of acquisition, low immunogenicity, and high proliferative ability. Here, we developed a poly(lactic- co-glycolic acid) (PLGA) nanoparticle with a layer of plasma membrane from umbilical cord MSC coating on the surface for tumor-targeted delivery of chemotherapy. Functionalization of MSC plasma membrane significantly enhanced the cellular uptake efficiency of PLGA nanoparticles, the tumor cell killing efficacy of PLGA-encapsulated doxorubicin, and most importantly the tumor-targeting and accumulation of the nanoparticles. As a result, this MSC-mimicking nanoformulation led to remarkable tumor growth inhibition and induced obvious apoptosis within tumor lesions. This study for the first time demonstrated the great potential of umbilical cord MSC plasma membranes in functionalizing nanocarriers with inherent tumor-homing features and the high feasibility of such biomimetic nanoformulations in cancer therapy.

Biomimetic nanoparticles with enhanced affinity towards activated endothelium as versatile tools for theranostic drug delivery.

Activation of the vascular endothelium is characterized by increased expression of vascular adhesion molecules and chemokines. This activation occurs early in the progression of several diseases and triggers the recruitment of leukocytes. Inspired by the tropism of leukocytes, we investigated leukocyte-based biomimetic nanoparticles (i.e., leukosomes) as a novel theranostic platform for inflammatory diseases. Methods: Leukosomes were assembled by combining phospholipids and membrane proteins from leukocytes. For imaging applications, phospholipids modified with rhodamine and gadolinium were used. Leukosomes incubated with antibodies blocking lymphocyte function-associated antigen 1 (LFA-1) and CD45 were administered to explore their roles in targeting inflammation. In addition, relaxometric assessment of NPs was evaluated. Results: Liposomes and leukosomes were both spherical in shape with sizes ranging from 140-170 nm. Both NPs successfully integrated 8 and 13 µg of rhodamine and gadolinium, respectively, and demonstrated less than 4% variation in physicochemical features. Leukosomes demonstrated a 16-fold increase in breast tumor accumulation relative to liposomes. Furthermore, quantification of leukosomes in tumor vessels demonstrated a 4.5-fold increase in vessel lumens and a 14-fold increase in vessel walls. Investigating the targeting mechanism of action revealed that blockage of LFA-1 on leukosomes resulted in a 95% decrease in tumor accumulation. Whereas blockage of CD45 yielded a 60% decrease in targeting and significant increases in liver and spleen accumulation. In addition, when administered in mice with atherosclerotic plaques, leukosomes exhibited a 4-fold increase in the targeting of inflammatory vascular lesions. Lastly, relaxometric assessment of NPs demonstrated that the incorporation of membrane proteins into leukosomes did not impact the r1 and r2 relaxivities of the NPs, demonstrating 6 and 30 mM-1s-1, respectively. Conclusion: Our study demonstrates the ability of leukosomes to target activated vasculature and exhibit superior accumulation in tumors and vascular lesions. The versatility of the phospholipid backbone within leukosomes permits the incorporation of various contrast agents. Furthermore, leukosomes can potentially be loaded with therapeutics possessing diverse physical properties and thus warrant further investigation toward the development of powerful theranostic agents.

Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs.

Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL-1 ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine.