Available online at www.sciencedirect.

com

ScienceDirect
Biological nanoparticles and their influence on organisms
Sarah Stanley
Over millions of years, biological systems have evolved wide
varieties of nanoparticles. Naturally occurring nanoparticles
show great diversity: they may be intracellular or extracellular,
formed of organic or inorganic materials and have wide-ranging
biological roles. Despite this diversity, nanoparticles found in
nature possess several characteristics that make them
attractive for biomedical purposes. This review presents an
overview of the most common biological nanoparticles and
outlines the potential applications of natural and modified
biological nanoparticles.
Addresses
Laboratory of Molecular Genetics, Rockefeller University, New York, NY
10065, USA
Corresponding author: Stanley, Sarah (sstanley@mail.rockefeller.edu)

Current Opinion in Biotechnology 2014, 28:6974

This review comes from a themed issue on Nanobiotechnology

cells, neurons [3], adipocytes [4], mesenchymal stem cells

[5] and endothelial cells, in addition to tumour cells [6].
They are also released into many body fluids such as
plasma, urine, saliva, cerebrospinal fluid, breast milk, and
amniotic and ascitic fluid [7].
Exosomes are formed by budding of the endosomal membrane into the lumen to form multivesicular bodies which
are then released at the cell surface [8]. Exosomes are
characterized by a lipid bilayer outer surface, by their size
of approximately 50160 nm and by their density (1.13
1.19 g/ml) [9]. Exosome membranes have a unique composition with some highly conserved proteins common to
many exosomes and others that depend on the type and
state of the cell of origin. The exosomal membranes
also have a high content of cholesterol and sphingolipids
associated with lipid rafts, ceramide and phosphoglycerides with long and saturated fatty-acyl chains [10] in
addition to a number of saccharide groups [11].

Edited by Jonathan S Dordick and Kelvin H Lee

For a complete overview see the Issue and the Editorial
Available online 8th January 2014
0958-1669/$ see front matter, # 2013 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.copbio.2013.11.014

Introduction
Nanotechnology research has primarily focused on manmade particles, but naturally occurring nanoparticles have
been present for millions of years [1]. A naturally occurring nanoparticle is an assembly of molecules or atoms,
synthesized in a biological system, with at least one
dimension in the 1100 nm range. These particles include intracellular structures such as magnetosomes and
extracellular assemblies such as lipoproteins and viruses.
Their functions are diverse, ranging from mineral storage
depots to intercellular communication. The aims of this
review were twofold: first, to give an overview of nanoparticles that occur in biological systems, their formation
and biological function and second, to describe how these
biological nanoparticles are being modified and used for
biomedical applications.

Exosomes encapsulate significant numbers of proteins

and nucleic acids. On the basis of their size, it is estimated
that exosomes may transport up to 100 proteins and
10 000 nucleotides. Exosomes have been demonstrated
to contain mRNA, miRNA and other non-coding RNAs.
Much of these are in short fragments (<200 nt) but intact,
coding RNA molecules also exist [12]. The similarity of
the exosome RNA content to the RNA population in the
original cell varies. Tumour cell exosomes have miRNA
composition similar to that of the parent cell, while
exosomes from other cell types contain RNA species that
differ from the parental cell [13].

Exosomes

Many biological roles have been ascribed to exosomes. In

some cells, exosomes are a mechanism for removal of
unwanted membrane proteins and mRNA [11]. Many
studies have demonstrated that exosomes play a role in
the immune response through antigen presentation [14].
In addition, exosomes have been reported to influence
inflammation, apoptosis and coagulation [9]. Growth factors such as TGF-b and epidermal growth factor have
been associated with exosomes and act as mediators of
cell signalling. In addition, exosomes may deliver nucleic
acids, including viral miRNAs if cells are infected [15], to
multiple anatomic sites often in a targeted fashion whose
mechanism remains unknown.

Among the many vesicles and macromolecules secreted

by cells are nanometer-sized bodies known as exosomes.
These were first described in the 1980s as nanovesicles
released by exocytosis from reticulocytes [2]. These small
vesicles are released by most cells in culture and a range
of cell types in vivo including B cells, dendritic and mast

Exosomes have several features that make them useful

for biomedical purposes. Since many body fluids contain
exosomes encapsulating miRNA, they may be useful as
early biomarkers of disease [16]. These may be particularly useful for diagnosis and prognostication of not only

www.sciencedirect.com

Current Opinion in Biotechnology 2014, 28:6974

70 Nanobiotechnology

malignancy [6] but also diseases such as Alzheimers

disease [17]. The role of exosomes in antigen presentation also makes them valuable in vaccination, both for
infectious diseases and for tumours. In particular, they
present antigens for long periods and are very stable.
Current trials include using autologous dendritic cellderived exosomes to which a tumour antigen has been
attached for use as a tumour vaccine for small cell lung
carcinoma and melanoma [18]. Finally, they may also
offer a mechanism for targeted protein or nucleic acid
delivery. The exosome contents are protected from
degradation and are not endocytosed by macrophages,
so they have a long circulating half-life, achieve a higher
concentration and are less toxic. Recent work has used
modified dendritic cells to release exosomes with a surface neuron-specific protein loaded with synthetic siRNA
for targeted CNS gene knockdown [19]. Further studies
are examining the utility of using synthetic exosomes for
targeted delivery of drugs from anti-inflammatory agents
such as curcumin to nucleic acid chelators in malignancy
[20].

Lipoproteins
Lipoproteins are complex self-assembling structures of
lipids and specialized proteins, apolipoproteins, that
transport water-insoluble lipids in the aqueous internal
environment of vertebrates and insects. Lipids and apolipoproteins form coreshell spherical or discoidal nanoparticles of 7 to >80 nm (see Table 1). They are
comprised of a core of non-polar lipids, triacylglyerols
and esterified cholesterol with a surface layer of apolipoproteins, phospholipids and non-esterified cholesterol
[21].
Lipoproteins are synthesized primarily by the liver and
intestines and change in structure and composition as
their components are used by peripheral tissues. Lipoproteins are defined by their size, density and protein
content (see Table 1). The largest, least dense lipoproteins are chylomicrons (CM). These are formed from
dietary free fatty acids and monoacylglycerols converted
to triacylglycerols (TAG) in the enterocytes. TAG is then
packaged with dietary cholesterol and apolipoprotein B48 [22]. Next are very low density lipoproteins (VLDL)

which are smaller and denser. These particles transport

endogenous TAG, cholesterol esters and fat-soluble vitamins from the liver to peripheral tissues with apolipoprotein B-100. In the periphery, TAG is hydrolysed by
lipoprotein lipase found on the surface of vascular endothelial cells. Removal of TAG, with protein and phospholipid transfer to high density lipoproteins (HDL),
converts VLDL into smaller, denser low density lipoproteins (LDL) [23]. LDL are composed of cholesterol and
cholesterol esters along with ApoB-100 and transport
cholesterol to the adrenals and adipose tissue [24].
Finally, HDL are the smallest, densest particles (Table
1) with the highest protein content and transport cholesterol from peripheral tissue to the liver. HDL are synthesized in the liver and then cholesterol from peripheral
cell surface membranes is added before the cholesterolloaded HDL particles return to the liver to be degraded
[25].
The self-assembly of lipoproteins, their ability to target
specific tissues and their capacity to carry hydrophobic
cargo have provoked considerable interest in their use for
diagnostic and therapeutic purposes. Reconstitution of
isolated, dehydrated human phospholipids and apolipoproteins results in self-assembled HDL [26]. Since then,
other studies have used modified apoplipoproteins and
natural or synthetic lipids to form reconstituted HDL
(rHDL). These form stable discoidal nanoparticles that
can be modified in size according to the protein to lipid
ratio, the lipid type and the apolipoproteins incorporated
[27].
rHDL have been used for both research and therapeutic
purposes. In vitro studies use rHDL as a stable environment for membrane-associated proteins, allowing
analyses of their secondary and tertiary structure [28].
HDL adsorbed onto hydrophilic surfaces act to immobilize membrane components such as receptors for highthroughput binding assays. In vivo, rHDL have been used
as contrast agents and for therapeutic purposes. For
imaging, contrast-generating agents can be attached to
the protein component of the reconstituted lipoprotein,
for example, gadolinium for MRI or unstable 123I for
nuclear imaging. Alternatively, contrast agents can be

Table 1
Composition and physical properties of lipoproteins

Chylomicrons
Very low density
lipoproteins (VLDL)
Low density
lipoproteins (LDL)
High density
lipoproteins (HDL)

Size (nm)

Density (g/ml)

Total lipid
content (wt%)

200600
60

<0.94
0.941.006

99
91

Cholesterol
ester content (wt%)

Triacylglycerol
content (wt%)

Apolipoproteins

3
18

85
55

A4, B48, C1, C2, C3

B100, C1, C2, C3
B100, a

25

1.0061.063

80

50

10

712

1.0631.210

44

40

Current Opinion in Biotechnology 2014, 28:6974

A1, A2, A5, D, E, M

www.sciencedirect.com

Biological nanoparticles and their roles in vivo Stanley 71

added to the lipoprotein core using hydrophobically

coated inorganic nanocrystals such as gold or iron oxide
[29]. Modification of the lipoprotein shell allows targeted
cell uptake, for example, by macrophages in atherosclerotic plaques [30].
HDL are also proposed as therapies for infections and for
drug delivery. Unmodified HDL nanoparticles bind lipopolysaccharide, released from gram negative bacteria, to
prevent overstimulation of the immune system [31].
HDL nanoparticles can also be used as decoys to prevent
damage to healthy cells either by viruses or toxins that
bind to specific cell surface proteins. Further, incorporating membrane components from pathogens in rHDL
particles allows their use as vaccines [32]. Other bioactive lipid moieties can also be incorporated into rHDL
particles. For example, incorporation of sphingosine-1phosphate into the lipoprotein shell induces endothelial
cell proliferation and tube formation that may be
applicable to acute coronary syndromes.
The lipoprotein core can also be used for therapeutic
delivery of lipophilic drugs to increase their solubility
and bioavailability and to reduce toxicity [33]. Several
compounds have been successfully incorporated into
HDL. These include delivery of amphotericin B to
treat fungal and protozoal infections in mice without
the toxicity normally associated with amphotericin B.
Modified surface apolipoproteins may also direct therapies to defined cell types. With the development of
mechanisms for controlled release, reconstituted lipoproteins may form even more valuable tools for therapy
delivery [27].

Ferritin
In addition to organic nanoparticles, organisms also produce inorganic nanoparticles, in particular iron-containing
particles such as ferrihydrite and magnetite. Ferritin is
expressed in bacteria, archaea and eukaryotes. Its primary
functions are as a protein nanocage to synthesize and store
iron oxides and to sequester potentially damaging iron
ions [34]. In eukaryotes, ferritin is a protein complex
composed of 24 subunits organized into a four-helical
bundle to form a hollow, symmetrical, almost spherical
protein shell of 12 nm. The interior cavity may accommodate up to 4500 Fe atoms. In eukaryotes, there are two
major ferritin genes encoding heavy (H) and light (L)
chains with differing properties (the L chain lacks the
catalytic activity of the H chain) that assemble to form
heteropolymers. The ratio of H to L chains varies from
tissue to tissue to form a wide range of isoferritins [35].
Ferritin acts as an iron storage molecule and prevents
generation of hydroxyl radicals by oxidation of Fe(II) to
Fe(III). In ferritin with high H chain content and catalytic
activity, highly ordered ferric oxohydroxide, is formed but
in ferritin with high L chain content, the crystal structure
www.sciencedirect.com

is more disordered. The magnetic properties of the ferritin core are complex. It is thought that the Fe(III) ions are
antiferromagnetically coupled with a superparamagnetic
moment [36]. Release of iron from ferritin requires electrons, protons and water release, although little is known
about the process. Iron exits through channels in the
ferritin shell or by proteolytic degradation of ferritin,
possibly in lysosomes [37].
In addition to H and L chains, mitochondrial ferritin, with
an N-terminal extension and mitochondrial localization
signal, has been identified in humans and mice. This
protein has ferroxidase activity and the ability to sequester iron. In humans, it is present in testis and spermatozoa
and in mice it is also found in heart, CNS, kidney and
pancreatic islets. Mitochondria produce high levels of
reactive oxygen species and also need iron for enzymes,
suggesting the mitochondrial ferritin may have both iron
storage and antioxidant roles [38].
The apoferritin shell can be used as a chamber for the
synthesis of nanoparticles. Metal nanoparticles with Cr,
Co, In oxides and nickel hydroxide and semiconductor
nanoparticles have been made in ex vivo horse spleen
apoferritin. Using the apoferritin shell produces nanoparticles with highly reproducible shape and size. In
addition, ferritin shells can be adsorbed in a defined
arrangement either using their negative charge or by
modification of the ferritin subunit, for example, to include a hydrophobic terminal to bind to carbonaeous
material or titanium binding peptides. The protein shells
can subsequently be removed to leave the nanoparticles
in situ [39]. Arrays of ferritin nanoparticles have been used
for several purposes, from carbon nanotube growth to
nanodisk fabrication and development of a bionanobattery [40].
The ferritin iron oxide core makes it an attractive candidate for development of MR contrast agents. Endogenous
ferritin is detectable by MRI and can be used as a cell
marker [41]. Modified ferritin, with N,N dimethyl-1,3
propanediamine (DMPA) coupled to surface proteins,
was used to detect negatively charged basement membranes, while addition of biotinylated peptides allows
targeting to specific cells [30]. Modification of the ferritin
shell to alter its catalytic activity allows the iron core to be
replaced by gadolinium for imaging, photosensitizers and
drugs for tumours, and quantum dots for imaging [42].
Ferritin has also been used to transduce the effects of
radiofrequency fields into channel activation to control
transgene expression in vitro [43].

Magnetite
While almost all bacteria have ferritin, a specialized group
of magnetotactic bacteria have evolved an additional ironcontaining nanoparticle [44]. These bacteria have a
specialized organelle, the magnetosome, comprised of a
Current Opinion in Biotechnology 2014, 28:6974

72 Nanobiotechnology

lipid bilayer and containing magnetic iron-containing

minerals, magnetite or greigite. Magnetosomes are 50
70 nm in diameter and can form one or more chains,
aligning the bacteria to the earths magnetic field and
facilitating the bacteria in swimming to more oxygendepleted regions.
The magnetosome membrane is a lipid bilayer formed by
the invagination of the inner cell membrane. The membrane contains a unique set of 2040 proteins which have
been implicated in the formation of the membrane, in
regulating its size and shape and in controlling the formation of the magnetosome chain(s) (see [45] for
review). Iron uptake and subsequent magnetite formation
occur only when the environment is almost anaerobic.
The magnetotactic bacteria employ both common iron
transporters and unique transporters, such as MagA,
which may encode an ATP-dependent iron transporter
[46]. The mechanism for magnetite formation is not well
understood. Soluble cytoplasmic iron may be oxidized to
a ferrihydrite precursor, then moved into the magnetosome and reduced to magnetite. Alternatively, an ironcontaining ferritin-like protein and soluble iron co-precipitate, forming crystals at the cell membrane that mature in the magnetosome to magnetite. The initial
magnetite crystals formed are small and superparamagnetic, but once they are greater than 35 nm, they become
a stable single domain magnetic crystal [47].
Magnetite has also been detected in additional species. In
honey bees, 7.5 nm spherical magnetite particles are found
in iron deposition vesicles of trophocytes [48]. It is also
present in the denticles of certain marine mollusks [49] and
in the nasal region of birds such as Bobolinks and pigeons
[50]. Magnetite has also been extracted from human tissue,
including the hippocampus [51], and possibly also within
the plaques of Alzheimers disease [52]. Magnetite in
Bobolinks and pigeons has been implicated in their ability
to use magnetic fields for navigation [53], though the
evidence for the involvement of magnetite is incomplete
[54]. The role of magnetite in the human brain is
unknown, though it has been suggested that biogenic
magnetite may transduce magnetic signals produced by
neurons and astrocytes within the neocortex [55].
Magnetite nanoparticles from magnetotactic bacteria
have a narrow size distribution, uniform morphology
and lower toxicity than those produced by chemical
synthesis. Magnetosomes are being used for several in
vitro purposes including removal of heavy metals from
water by surface adsorption, magnetic separation, immunobinding, receptor binding assays, and DNA extraction.
In vivo, they have been studied as contrast agents for MRI
and may be useful for heating applications such as tumour
hyperthermia or regulated cell activation. Several of these
applications require functionalization of the magnetosome either by chemical coupling to lipids or proteins
Current Opinion in Biotechnology 2014, 28:6974

in the membrane or by binding to endogenous membrane

proteins [56]. However, the magnetosome membrane can
also be modified by transgenic expression of monomeric
camelid antibodies, resulting in genetically encoded
expression of a magnetosome surface antibody. Biogenic
magnetite itself can also be modified, for example, by
cross-linking to chitosan followed by coating with silver
nanoparticles for antibacterial uses or linking to trypsin
for protein digestion.

Viruses
Viruses, small infectious particles that require living cells
for replication, are highly diverse, naturally occurring
nanoparticles. They share a common structure of a shell
comprised of capsid proteins enclosing the DNA or RNA
viral genome. They span a wide variety of sizes (within
the nanometer range) and morphologies from simple
spheres to rods to icosahedrons. Viruses have been
described that target almost all known organisms and
tissues. Most applications use virus-like particles (VLP)
which are native viral capsid proteins without nucleic acid
and therefore do not cause infection [57].
Viruses and VLP have defined geometries, are very
uniform and have robust protein shells that can be modified for bioconjugation or for chemical modification,
allowing molecules to be displayed in a precise spatial
distribution. However, they can be difficult to produce in
bulk and there are limits to the size of antigen that can be
attached. In addition, virus capsid protein folding is not
always well understood. Bioconjugation to capsid lysine
or cysteine residues is relatively straightforward and
allows extensive attachment of molecules. The capsids
are stable over a wide range of temperatures and pH,
making them suitable for many applications.
Several in vitro applications of VLP have been described
including use as nanoreactors and as filamentous or
spherical scaffolds [42]. Modified VLP are also being
used in vivo. Their primary use has been in vaccination
either to induce immunity against the parent virus or to
modify other diseases [58]. VLP conjugated to appropriate epitopes have been used for anti-tumour vaccines and
for vaccines against chronic diseases such as hypertension. VLP have also been modified for use as contrast
agents in MRI, for example, by addition of gadolinium to
metal binding sites or conjugation of gadolinium chelates,
while VLP labelled with unstable isotopes of fluoride
have been used as PET contrast agents [30]. VLP can
also be modified to create hydrophobic pockets within the
protein shell which can be loaded with insoluble, hydrophobic drugs for delivery [59]. In addition, the natural
affinity of VLP for defined cell types allows targeted
delivery or the VLP can be modified by bioconjugation
to targeting molecules, such as folic acid, for cell-specific
delivery.
www.sciencedirect.com

Biological nanoparticles and their roles in vivo Stanley 73

Conclusion
Over the last few years, there have been many studies
aimed at increasing our understanding of the structure,
synthesis and physiological roles of naturally occurring
nanoparticles. Biologically produced nanoparticles are
highly diverse but also offer features that make them
attractive for biomedical uses: the uniformity of their
structure, low toxicity, ability to evade the immune
system and capacity for modification. These properties
are now beginning to be harnessed both for in vitro
systems such as diagnostics and for in vivo purposes. As
our knowledge of the biology of naturally occurring
nanoparticles expands and challenges related to synthesis
of such particles are overcome, it is likely that the biomedical applications of natural nanoparticles will expand
further.

References and recommended reading

Papers of particular interest, published within the period of review,
have been highlighted as:
 of special interest
 of outstanding interest

1.

Lippert PC, Zachos JC: A biogenic origin for anomalous finegrained magnetic material at the PaleoceneEocene boundary
at Wilson Lake, New Jersey. Paleoceanography 2007, 22:A4104.

2.

Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C: Vesicle

formation during reticulocyte maturation. Association of
plasma membrane activities with released vesicles
(exosomes). J Biol Chem 1987, 262:9412-9420.

3.

Von Bartheld CS, Altick AL: Multivesicular bodies in neurons:

distribution, protein content, and trafficking functions. Prog
Neurobiol 2011, 93:313-340.

4.

Muller G, Jung C, Straub J, Wied S, Kramer W: Induced release of

membrane vesicles from rat adipocytes containing
glycosylphosphatidylinositol-anchored microdomain and
lipid droplet signalling proteins. Cell Signal 2009,
21:324-338.

5.

Collet G, Grillon C, Nadim M, Kieda C: Trojan horse at cellular

level for tumor gene therapies. Gene 2013, 525:208-216.

6.

Suntres Z, Smith M, Momen-Heravi F, Hu J, Zhang X, Wu Y, Zhu H,

Wang J, Zhou J, Kuo W: Therapeutic uses of exosomes.
Exosomes Microvesicles 2013, 1 http://dx.doi.org/10.5772/56522.

7.

Van NG, Porto-Carreiro I, Simoes S, Raposo G: Exosomes: a

common pathway for a specialized function. J Biochem 2006,
140:13-21.

8.

Simons M, Raposo G: Exosomes vesicular carriers for

intercellular communication. Curr Opin Cell Biol 2009,
21:575-581.

9.

Vlassov AV, Magdaleno S, Setterquist R, Conrad R: Exosomes:

current knowledge of their composition, biological functions,
and diagnostic and therapeutic potentials. Biochim Biophys
Acta 2012, 1820:940-948.

10. Subra C, Laulagnier K, Perret B, Record M: Exosome lipidomics

unravels lipid sorting at the level of multivesicular bodies.
Biochimie 2007, 89:205-212.

13. Lages E, Ipas H, Guttin A, Nesr H, Berger F, Issartel JP:

MicroRNAs: molecular features and role in cancer. Front Biosci
(Landmark Ed) 2012, 17:2508-2540.
14. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R,
Harding CV, Melief CJ, Geuze HJ: B lymphocytes secrete
antigen-presenting vesicles. J Exp Med 1996,
183:1161-1172.
15. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van
Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD,
Wurdinger T, Middeldorp JM: Functional delivery of viral
miRNAs via exosomes. Proc Natl Acad Sci U S A 2010,
107:6328-6333.
16. Burger D, Schock S, Thompson CS, Montezano AC, Hakim AM,
Touyz RM: Microparticles: biomarkers and beyond. Clin Sci
(Lond) 2013, 124:423-441.
17. Cheng L, Quek CY, Sun X, Bellingham SA, Hill AF: The detection
of microRNA associated with Alzheimers disease in biological
fluids using next-generation sequencing technologies. Front
Genet 2013, 4:150.
18. Viaud S, Thery C, Ploix S, Tursz T, Lapierre V, Lantz O, Zitvogel L,
Chaput N: Dendritic cell-derived exosomes for cancer
immunotherapy: whats next? Cancer Res 2010, 70:1281-1285.
19. varez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ:
 Delivery of siRNA to the mouse brain by systemic injection of
targeted exosomes. Nat Biotechnol 2011, 29:341-345.
Description of targeted nucleic acid delivery in vivo using modified
autologous exosomes derived from dendritic cells.
20. Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY, Park J, Nilsson J,
Lotvall J, Kim YK, Gho YS: Bioinspired exosome-mimetic
nanovesicles for targeted delivery of chemotherapeutics to
malignant tumors. ACS Nano 2013, 7(9):7698-7710.
21. Jonas A, Phillips MC: Lipoprotein structure. In Biochemistry of
Lipids, Lipoproteins and Membranes. Edited by Vance DE, Vance
JE. Amsterdam: Elsevier Science; 2008:485-506.
22. Mansbach CM, Siddiqi SA: The biogenesis of chylomicrons.
Annu Rev Physiol 2010, 72:315-333.
23. Blasiole DA, Davis RA, Attie AD: The physiological and
molecular regulation of lipoprotein assembly and secretion.
Mol Biosyst 2007, 3:608-619.
24. Hevonoja T, Pentikainen MO, Hyvonen MT, Kovanen PT, AlaKorpela M: Structure of low density lipoprotein (LDL) particles:
basis for understained molecular changes in modified LDL.
Biochim Biophys Acta 2000, 1488:189-210.
25. Phillips MC: New insights into the determination of HDL
structure by apolipoproteins. J Lipid Res 2013,
54:2034-2048.
26. Scanu A: Binding of human serum high density lipoprotein
apoprotein with aqueous dispersions of phospholipids. J Biol
Chem 1967, 242:711-719.
27. Ryan RO: Nanobiotechnology applications of reconstituted
high density lipoprotein. J Nanobiotechnol 2010, 8:28.
28. Leitz A, Bayburt T, Barnakov A, Springer B, Sligar S: Functional
reconstitution of beta2-adrenergic receptors utilizing selfassembling nanodisc technology. Biotechniques 2006, 40:601610.
29. Damiano MG, Mutharasan RK, Tripathy S, McMahon KM,
Thaxton CS: Templated high density lipoprotein nanoparticles
as potential therapies and for molecular delivery. Adv Drug
Deliv Rev 2013, 65:649-662.

11. Batista BS, Eng WS, Pilobello KT, Hendricks-Munoz KD, Mahal LK:
Identification of a conserved glycan signature for
microvesicles. J Proteome Res 2011, 10:4624-4633.

30. Cormode DP, Jarzyna PA, Mulder WJM, Fayad ZA: Modified

natural nanoparticles as contrast agents for medical imaging.
Adv Enzyme Regul 2010, 62:329-338.
Excellent summary of use of biological nanoparticles, particularly lipoproteins, for imaging applications.

12. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO:

Exosome-mediated transfer of mRNAs and microRNAs is a
novel mechanism of genetic exchange between cells. Nat Cell
Biol 2007, 9:654-659.

31. Parker T, Levine D, Chang J, Laxer J, Coffin C, Rubin A:

Reconstituted high-density lipoprotein neutralizes gramnegative bacterial lipopolysaccharides in human whole blood.
Infect Immun 1995, 63:253-258.

www.sciencedirect.com

Current Opinion in Biotechnology 2014, 28:6974

74 Nanobiotechnology

32. Bricarello DA, Smilowitz JT, Zivkovic AM, German JB, Parikh AN:

Reconstituted lipoprotein: a versatile class of biologicallyinspired nanostructures. ACS Nano 2011, 5:42-57.
Overview of synthesis and application of rHDL particles for biomedical
applications.
33. Lou B, Liao X, Wu M, Cheng P, Yin C, Fei Z: High-density
lipoprotein as a potential carrier for delivery of a lipophilic
antitumoral drug into hepatoma cells. World J Gastroenterol
2005, 11:954-959.
34. Theil EC: Ferritin: the protein nanocage and iron biomineral in
health and in disease. Inorg Chem 2013, 52:12223-12233.
35. Zhang Y, Orner BP: Self-assembly in the ferritin nano-cage
protein superfamily. Int J Mol Sci 2011, 12:5406-5421.

Interesting article describing functional analysis of the genes of the

magnetosome island in the formation and structure of the magnetosome.
46. Nakamura C, Burgess JG, Matsunaga T: An iron-regualted gene,
magA, encoding an iron transport protein of Magnetospirillum
magneticuum AMB-1. J Biol Chem 1995, 118:23-27.
47. Arakaki A, Nakazawa H, Nemoto M, Mori T, Matsunaga T:
Formation of magnetite by bacteria and its application. J R Soc
Interface 2008, 5:977-999.
48. Hsu CY, Chan YP: Identification and localization of proteins
associated with biomineralization in the iron deposition
vesicles of honeybees (Apis mellifera). PLoS ONE 2011,
6:e19088.

36. Papaefthymiou GC: The Mossbauer and magnetic properties of

ferritin cores. Biochim Biophys Acta 2010, 1800:886-897.

49. Saunders M, Kong C, Shaw JA, Macey DJ, Clode PL:

Characterization of biominerals in the radula teeth of the
chiton, Acanthopleura hirtosa. J Struct Biol 2009, 167:55-61.

37. Theil EC: Ferritin protein nanocages use ion channels, catalytic

sites and nucleation channels to manage iron/oxygen
chemistry. Curr Opin Cell Biol 2011, 15:304-311.
Comprehensive and accessible description of iron oxide nanoparticle
formation in ferritin protein complexes.

50. Wiltschko R, Wiltschko W: The magnetite-based receptors in

the beak of birds and their role in avian navigation. J Comp
Physiol A Neuroethol Sens Neural Behav Physiol 2013,
199:89-98.

38. Arosio P, Levi S: Cytosolic and mitochondrial ferritins in the

regulation of cellular iron homeostasis and oxidative damage.
Biochim Biophys Acta 2010, 1800:783-792.

51. Dobson J: Nanoscale biogenic iron oxides and

neurodegenerative disease. FEBS Lett 2001, 496:1-5.

39. Yamashita H, Iwahori K, Kumagai S: Ferritin in the field of

nanodevices. Biochim Biophys Acta 2010, 1800(8):846-857.
40. Watt GD, Kim J-W, Zhang B, Miller T, Harb JN, Davis RC, Choi SH:
A protein-based ferritin bio-nanobattery. J Nanotechnol 2012,
2012 http://dx.doi.org/10.1155/2012/516309 9 pages (Article ID
516309).
41. Kim HS, Joo HJ, Woo JS, Choi YS, Choi SH, Kim H, Moon WK: In
vivo magnetic resonance imaging of transgenic mice
expressing human ferritin. Mol Imaging Biol 2013, 15:48-57.
42. Doll TAPF, Raman S, Dey R, Burkhard P: Nanoscale assemblies
and their biomedical applications. J R Soc Interface 2013,
10(80):20120740.
43. Stanley SA, Gagner JE, Damanpour S, Yoshida M, Dordick JS,
Friedman JM: Radiowave heating of iron oxide nanoparticles
can regulated plasma glucose in mice. Science 2012,
336:604-607.
44. Lefevre CT, Bazylinski DA: Ecology, diversity and evolution of
magnetotactic bacteria. Microbiol Mol Biol Rev 2013, 77:497-526.
45. Murat D, Quinlan A, Vali H, Komeili A: Comprehensive genetic

dissection of the magnetosome gene island reveals the
stepwise assembly of a prokaryotic organelle. Proc Natl Acad
Sci U S A 2010, 107:5593-5598.

Current Opinion in Biotechnology 2014, 28:6974

52. Dobson J: Magnetic iron compounds in neurological

disorders. Ann N Y Acad Sci 2004, 1012:183-192.
53. Beason R, Dussourd N, Deutschlander M: Behavioural evidence
for the use of magnetic material in magnetoreception by a
migratory bird. J Exp Biol 1995, 198:141-146.
54. Wu LQ, Dickman JD: Neural correlates of a magnetic sense.
 Science 2012, 336:1054-1057.
Exciting study providing evidence of neural involvement in the vertebrate
sensing of magnetic fields.
55. Banaclocha MAM, Bokkon I, Martinez-Banaclocha H: Long-term
memory in brain magnetite. Med Hypotheses 2010, 74:254-257.
56. Lang C, Schuler D, Faivre D: Synthesis of magnetite
nanoparticles for bio- and nanotechnology: genetic
engineering and biomimetics of bacterial magnetosomes.
Macromol Biosci 2007, 7:144-151.
57. Zeltins A: Construction and characterization of virus-like
particles: a review. Mol Biotechnol 2013, 53:92-107.
58. Gregory AE, Titball R, Williamson D: Vaccine delivery using
nanoparticles. Front Cell Infect Microbiol 2013, 3:13.
59. Yoo JW, Irvine DJ, Discher DE, Mitragotri S: Bio-inspired,
bioengineered and biomimetic drug delivery carriers. Nat Rev
Drug Discov 2011, 10:521-535.

www.sciencedirect.com