Complement-dependent uptake of nanoparticles by blood phagocytes: brief overview and perspective.

Immune recognition and uptake of nanoparticles remain the hot topic in nanomedicine research. Complement is the central player in the immune recognition of engineered nanoparticles. Here, we summarize the accumulated knowledge on the role of complement in the interactions of nanomaterials with blood phagocytes.

High-resolution bioenergetics correlates the length of continuous protonatable diaminoethane motif of four-armed oligo(ethanamino)amide transfectants to cytotoxicity.

Recent clinical success with Onpattro and cationic ionizable lipid nanoparticle-based mRNA vaccines has rejuvenated research in the design and engineering of broader synthetic cationic vectors for nucleic acid compaction and transfection. However, perturbation of metabolic processes and cytotoxicity are still of concern with synthetic cationic vectors. Here, through an integrated bioenergetic and biomembrane integrity probing in three different human cell lines we reveal the dynamic effect of a library of sequence-defined four-arm oligo(ethanamino)amide transfectant on cell homeostasis, and identify metabolically safe building units over wide concentration ranges.

PEGylation of Phosphatidylglycerol/Docosahexaenoic Acid Hexosomes with d-α-Tocopheryl Succinate Poly(ethylene glycol) Induces Morphological Transformation into Vesicles with Prolonged Circulation Times.

Considering the broad therapeutic potential of omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA), here we study the effect of PEGylation of DHA-incorporated hexosomes on their physicochemical characteristics and biodistribution following intravenous injection into mice. Hexosomes were formed from phosphatidylglycerol and DHA with a weight ratio of 3:2. PEGylation was achieved through the incorporation of either d-α-tocopheryl succinate poly(ethylene glycol) (TPGS-mPEG) or 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol) (DSPE-mPEG) at a concentration of 1.

Cell medium-dependent dynamic modulation of size and structural transformations of binary phospholipid/ω-3 fatty acid liquid crystalline nano-self-assemblies: Implications in interpretation of cell uptake studies.

Lyotropic non-lamellar liquid crystalline (LLC) nanoparticles, with their tunable structural features and capability of loading a wide range of drugs and reporter probes, are emerging as versatile injectable nanopharmaceuticals. Secondary emulsifiers, such as Pluronic block copolymers, are commonly used for colloidal stabilization of LLC nanoparticles, but their inclusion often compromises the biological safety (e.g.

A structurally diverse library of glycerol monooleate/oleic acid non-lamellar liquid crystalline nanodispersions stabilized with nonionic methoxypoly(ethylene glycol) (mPEG)-lipids showing variable complement activation properties.

Pluronic F127-stabilized non-lamellar liquid crystalline aqueous nanodispersions are promising injectable platforms for drug and contrast agent delivery. These nanodispersions, however, trigger complement activation in the human blood, where the extent of complement activation and opsonization processes may compromise their biological performance and safety. Here, we introduce a broad family of nanodispersions from glycerol monooleate (GMO) and oleic acid (OA) in different weight ratios, and stabilized with a plethora of nonionic methoxypoly(ethylene glycol) (mPEG)-lipids of different PEG chain length and variable lipid moiety (monounsaturated or saturated diglycerides or D-α-tocopheryl succinate).

Overcoming Nanoparticle-Mediated Complement Activation by Surface PEG Pairing.

Many PEGylated nanoparticles activate the complement system, which is an integral component of innate immunity. This is of concern as uncontrolled complement activation is potentially detrimental and contributes to disease pathogenesis. Here, it is demonstrated that, in contrast to carboxyPEG-stabilized poly(lactic--glycolic acid) nanoparticles, surface camouflaging with appropriate combinations and proportions of carboxyPEG and methoxyPEG can largely suppress nanoparticle-mediated complement activation through the lectin pathway.

Non-Lamellar Liquid Crystalline Nanocarriers for Thymoquinone Encapsulation.

Unlabelled: Owing to their unique structural features, non-lamellar liquid crystalline nanoparticles comprising cubosomes and hexosomes are attracting increasing attention as versatile investigative drug carriers.

Background: Depending on their physiochemical characteristics, drug molecules on entrapment can modulate and reorganize structural features of cubosomes and hexosomes. Therefore, it is important to assess the effect of guest molecules on broader biophysical characteristics of non-lamellar liquid crystalline nanoparticles, since drug-induced architectural, morphological, and size modifications can affect the biological performance of cubosomes and hexosomes.

Publisher Correction: On the issue of transparency and reproducibility in nanomedicine.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Perturbation of mitochondrial bioenergetics by polycations counteracts resistance to BRAF inhibition in melanoma cells.

Acquired resistance to the oncogenic BRAF inhibitor vemurafenib is a major clinical challenge in the treatment of melanoma. Vemurafenib resistance is poorly understood; however, available evidence indicates that reprogrammed mitochondrial metabolism could contribute to the resistance mechanism. Here we show that synthetic polycations, such as polyethylenimines and poly(l-lysine)s, prevent vemurafenib resistance in melanoma cells through induction of mitochondrial bioenergetic crisis.

Publisher Correction: Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.

In the version of this Article originally published, a technical error led to Fig. 1a containing '!!!!!!!!' above the scale bar. This has now been corrected in all versions of the Article.

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.

Deposition of complement factors (opsonization) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonization of superparamagnetic iron oxide (SPIO) nanoworms with the third complement protein (C3) was dependent on the biomolecule corona of the nanoparticles. Here we show that natural antibodies play a critical role in C3 opsonization of SPIO nanoworms and a range of clinically approved nanopharmaceuticals.

Pharmacokinetic analysis reveals limitations and opportunities for nanomedicine targeting of endothelial and extravascular compartments of tumours.

Targeting of nanoparticles to tumours can potentially improve the specificity of imaging and treatments. We have developed a multicompartmental pharmacokinetic model in order to analyse some of the factors that control efficiency of targeting to intravascular (endothelium) and extravascular (tumour cells and stroma) compartments. We make the assumption that transport across tumour endothelium is an important step for subsequent nanoparticle accumulation in the tumour (area-under-the-curve, AUC) regardless of entry route (interendothelial and transendothelial routes) and study this through a multicompartmental simulation.

Multivalent targeting and killing of HER2 overexpressing breast carcinoma cells with methotrexate-encapsulated tetra-specific non-overlapping variable domain heavy chain anti-HER2 antibody-PEG-liposomes: In vitro proof-of-concept.

The variable domain of the heavy chain antibodies (VHHs) is the smallest (15 kDa) intact single domain antigen-binding fragment. VHHs often exhibit sub-nanomolar affinity for their designated targets and therefore are receiving increasing attention in molecular targeting and nanomedicine engineering. We cloned and expressed four non-overlapping anti-HER2 VHHs in a prokaryotic expression system that yielded disulfide-bonded VHHs.

Cisplatin Encapsulation Generates Morphologically Different Multicompartments in the Internal Nanostructures of Nonlamellar Liquid-Crystalline Self-Assemblies.

Cisplatin ( cis-diamminedichloroplatinum(II)) is among the most potent cytotoxic agents used in cancer chemotherapy. The encapsulation of cisplatin in lipid-based drug carriers has been challenging owing to its low solubility in both aqueous and lipid phases. Here, we investigated cisplatin encapsulation in nonlamellar liquid-crystalline (LC) nanodispersions formed from a ternary mixture of phytantriol (PHYT), vitamin E (Vit E), and an anionic phospholipid [either phosphatidylglycerol (DSPG) or phosphatidylserine (DPPS)].

C1q-Mediated Complement Activation and C3 Opsonization Trigger Recognition of Stealth Poly(2-methyl-2-oxazoline)-Coated Silica Nanoparticles by Human Phagocytes.

Poly(2-methyl-2-oxazoline) (PMOXA) is an alternative promising polymer to poly(ethylene glycol) (PEG) for design and engineering of macrophage-evading nanoparticles (NPs). Although PMOXA-engineered NPs have shown comparable pharmacokinetics and in vivo performance to PEGylated stealth NPs in the murine model, its interaction with elements of the human innate immune system has not been studied. From a translational angle, we studied the interaction of fully characterized PMOXA-coated vinyltriethoxysilane-derived organically modified silica NPs (PMOXA-coated NPs) of approximately 100 nm in diameter with human complement system, blood leukocytes, and macrophages and compared their performance with PEGylated and uncoated NP counterparts.

Nanomedicine safety in preclinical and clinical development: focus on idiosyncratic injection/infusion reactions.

Injection/infusion reactions to nanopharmaceuticals (and particulate drug carriers) are idiosyncratic and well documented. The molecular basis of nanoparticle-mediated injection reactions is debatable, with two hypotheses as front-runners. The first is complement-activation-related 'pseudoallergy', where a causal role for nanoparticle-mediated complement activation in injection/infusion reactions is considered.

Revealing Dynamics of Accumulation of Systemically Injected Liposomes in the Skin by Intravital Microscopy.

Accumulation of intravenously injected cytotoxic liposomes in the skin induces serious toxicity. We used single time point and longitudinal intravital microscopy to understand skin accumulation dynamics of non-PEGylated and PEGylated liposomes after systemic injection into mice. Non-PEGylated egg phosphatidylcholine (PC) liposomes showed short circulation half-life (1.

Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice.

Archaeal viruses offer exceptional biophysical properties for modification and exploration of their potential in bionanotechnology, bioengineering and nanotherapeutic developments. However, the interaction of archaeal viruses with elements of the innate immune system has not been explored, which is a necessary prerequisite if their potential for biomedical applications to be realized. Here we show complement activation through lectin (via direct binding of MBL/MASPs) and alternative pathways by two extremophilic archaeal viruses (Sulfolobus monocaudavirus 1 and Sulfolobus spindle-shaped virus 2) in human serum.

Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation.

Polyplex Evolution: Understanding Biology, Optimizing Performance.

Polyethylenimine (PEI) is a gold standard polycationic transfectant. However, the highly efficient transfecting activity of PEI and many of its derivatives is accompanied by serious cytotoxic complications and safety concerns at innate immune levels, which impedes the development of therapeutic polycationic nucleic acid carriers in general and their clinical applications. In recent years, the dilemma between transfection efficacy and adverse PEI activities has been addressed from in-depth investigations of cellular processes during transfection and elucidation of molecular mechanisms of PEI-mediated toxicity and translation of these integrated events to chemical engineering of novel PEI derivatives with an improved benefit-to-risk ratio.