Lignin Nanoparticles Enter The Scene A Promising Versatile Green Tool For Multiple Applications

Biotechnology Advances 47 (2021) 107685
Contents lists available at ScienceDirect
Biotechnology Advances
journal homepage: www.elsevier.com/locate/biotechadv
Research review paper
Lignin nanoparticles enter the scene: A promising versatile green tool for
multiple applications
Willian Daniel Hahn Schneider *, Aldo José Pinheiro Dillon, Marli Camassola
Enzymes and Biomass Laboratory, Institute of Biotechnology, University of Caxias do Sul, Francisco Getúlio Vargas Street, 1130, 95070-560 Caxias do Sul, RS, Brazil
A R T I C L E I N F O A B S T R A C T
Keywords: Strategies to take advantage of residual lignin from industrial processes are well regarded in the field of green
Nanospheres chemistry and biotechnology. Quite recently, researchers transformed lignin into nanomaterials, such as nano
Nanofibers particles, nanofibers, nanofilms, nanocapsules and nanotubes, attracting increasing attention from the scientific
Nanocapsules
community. Lignin nanoparticles are seen as green way to use high-value renewable resources for application in
Nanocomposite
different fields because recent studies have shown they are non-toxic in reasonable concentrations (both in vitro
Nanomicelles
Drug delivery and in vivo assays), inexpensive (a waste generated in the biorefinery, for example, from the bioethanol plat
Antioxidant, UV-protectant sunscreen form) and potentially biodegradable (by fungi and bacteria in nature). Promising studies have tested lignin
Antimicrobial nanoparticles for antioxidants, UV-protectants, heavy metal absorption, antimicrobials, drugs carriers, gene
Encapsulation delivery systems, encapsulation of molecules, biocatalysts, supercapacitors, tissue engineering, hybrid nano
composites, wound dressing, and others. These nanoparticles can be produced from distinct lignin types and by
different chemical/physical/biological methods, which will result in varied characteristics for their morphology,
shape, size, yield and stability. Therefore, taking into account that the theme “lignin nanoparticles” is a trending
topic, this present review is emerging and has the discuss the current status, covering from concepts, the for
mation mechanism, synthesis methods and applications, to the future perspectives and challenges linked to
lignin-based nanomaterials, aiming at the viability and commercialization of this biotechnological product.
1. Introduction basic unit is called p-hydroxyphenyl (non-methoxylated, derived from

coumaryl alcohol, known as lignin H), guaiacil (with a methoxy, derived
Lignin is the second most abundant natural polymer in Earth, present from coniferyl alcohol, known as lignin G) or syringil (with two
in all types of plants (Becker and Wittmann, 2019) (Fig. 1A), and the methoxyls, derived from synaphyl alcohol, known as lignin S) (Carvalho
main available renewable resource based on aromatic units (Lievonen et al., 2009). The heterogeneity of lignin is characterized by the inter
et al., 2016; Schneider et al., 2020). Lignin is located in greater quantity action of H, G and S units (Laurichesse and Avérous, 2014), generating
in the secondary cell wall and widespread in the middle lamella different functional groups and linkages (Yang et al., 2018a) with the
(Fig. 1B), being commonly distributed in combination with hemicellu aryl ether β-O-4 bond (Fig. 2D) being the most present (about 50%).
lose around the cellulose fibrils (Fig. 1C). Its chemical structure leads to However, depending on the botanical origins of the lignin and the
increase the thickness of the cell wall and the typical recalcitrance in extraction and isolation process, this proportion can change (Laur
plants (Isikgor and Becer, 2015; Beckham et al., 2016; Wang et al., ichesse and Avérous, 2014; Zhao et al., 2017). For example, according to
2018). Moreover, lignin is also known to assist the plant in the defense of Zhao et al. (2017), in poplar lignin, β-β resinol linkage is predominant
pathogens and exposure to the most different climates (Wang et al., while β-O-4 is absent due to severe pulping conditions.
2018; Vance et al., 1980). Lignin typically comprises 20–32% of the lignocellulosic biomass by
Lignin is composed of an integrated network block of aromatic units weight (Chen et al., 2011) and the percentage of basic units of coumaryl
derived from the radical coupling of its phenylpropanoid monomers, (H), coniferyl (G) and synapyl (S) alcohol vary widely depending on the
known as precursor hydroxy-cinnamic alcohols: p-coumaryl, coniferyl plant material (Fig. 1E). For example, softwood lignins comprise more G
and synaphyl (Fig. 1D) (Fengel and Wegener, 1989; Carvalho et al., units, whereas hardwood lignins are composed by the same proportion
2009). Depending on the level of methoxylation of the aromatic ring, the of both G and S units and herbaceous lignins contain all three units,
* Corresponding author.
E-mail addresses: willianschneiderwhs@yahoo.com.br, wdhschneider@ucs.br (W.D.H. Schneider).
https://doi.org/10.1016/j.biotechadv.2020.107685
Received 25 September 2020; Received in revised form 23 November 2020; Accepted 22 December 2020
Available online 29 December 2020
0734-9750/© 2020 Elsevier Inc. All rights reserved.
W.D.H. Schneider et al. Biotechnology Advances 47 (2021) 107685
Fig. 1. Overview of lignin. The occurrence of lignin in nature (A), its location on the cell wall (B) and shape (C), its chemical structure and the main linkages (D),
variation of the H, G and S units in different plant groups (E) and the use of lignin in different fields (F), highlighting the newest applications of this biopolymer in the
synthesis of lignin nanoparticles (LNPs).
2
mainly G and S (Li et al., 2015; Tian et al., 2017a, 2017b). (controlled release of pesticides and herbicides, sequestering agents for
Nearly 50 to 70 million tons of lignin is produced annually (Saratale heavy metal, as a component for humic acids formation in soil structures
et al., 2019). It represents the main unexploited by-product coming from and as high-value fertilizers); human health (drug encapsulation and
the pulp and paper industry (Tortora et al., 2014) and its chemical delivery, treatment of obesity, diabetes, thrombosis, viruses and cancer)
composition varies depending on wood species, process conditions and and others (UV-protectant cosmetics, cement, battery) (Fig. 1F) (Behin
extraction methods (Lintinen et al., 2016). In general, it can be classified and Sadeghi, 2016; Vinardell and Mitjans, 2017; Figueiredo et al., 2018;
into four categories (i.e., Kraft, lignosulfonate, soda, and organosolv Schneider et al., 2019a).
lignin) by sulfur or sulfur-free processes (Yang et al., 2018a; Doherty However, large particle size, heterogeneity, poor dispersibility and
et al., 2011). Most of the lignin is used for burning, due to its high heat irregular morphology are the factors limiting its use as a high value-
value and only 5% of the industrial lignin is used for value-added added material (Wang et al., 2019). To overcome this hindrance,
products (Lievonen et al., 2016). Currently, lignosulfonates dominate different chemical reactions can be used to modify lignin to produce
almost 80% of the market, however, with a growing trend in the lignin high-value materials, for example, lignin-based nanomaterials (Fig
market between 2023 and 2028, kraft lignin production is growing ueiredo et al., 2018). In the last years, lignin valorisation to value-added
faster, competing with lignosulfonates to some extent, due to its lower products, such as lignin nanomaterials, has been considered as an
cost and higher reactivity (Johansen, 2018; Dessebesell et al., 2020). essential process for sustainable biorefineries (Liu et al., 2019a).
When analysing bioethanol production from lignocellulosic biomass, Nanotechnology has many environmental advantages, and due to the
only 40% of the lignin is needed within a biomass heating plant to cover physical, chemical and biological properties of its performance it stands
the demand for thermal energy, that is, there is a surplus around 60% of out in comparison with macromaterials, for example (Gilca et al., 2015),
the lignin that can be valued beyond the carbohydrate fractions of in and came to break technological boundaries in the current century (Lu
terest. This lignin valorization is crucial to establish biorefineries and a et al., 2012a, 2012b). Specifically, nanoparticles relate to particles
bio-based economy (Koch et al., 2020). whose size are in the range from 1 to 1000 nm (Charinpanitkul et al.,
Because it is a bioresource and a low cost waste, lignin has a wide 2008) and there are already a handful studies involving metallic nano
range of properties and has always attracted the interest of researchers particles for the most different applications (Marulasiddeshwara et al.,
(Gilca et al., 2015; Kai et al., 2016b). Lignin has been considered as a 2017).
potential substitute for fossil fuels in the development of new materials However, in the last decade, there was a significant increase in the
or chemicals due to the low price, biodegradability and non-toxicity number of papers and patents highlighting the conversion of lignin to
(Zhang et al., 2019). It can be used in biofuels (diesel, syngas, functional materials (Kai et al., 2016a), such as lignin nanoparticles
hydrogen, char); chemicals (dispersant, binder, polymers); agriculture (LNPs). LNPs have the advantages of being a “green”, easy and
Fig. 2. Different applications of LNPs. These versatile green tools can be used in different fields, such as biofuels, biomedicine, pharmacy, agriculture, food, and
others. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
3
abundantly available, biocompatible and inexpensive nanomaterial micrometre. The second method was based on acid precipitation from
(Alqahtani et al., 2019), and recently, some applications of LNPs have alkali lignin solution. Since then, many other works on producing LNPs
been consolidated, such as their use in thermoplastics, nanocomposites, have been published, in which lignins from different resources and
foams, bactericides, products that require protection from UV radiation methods of production are used and different applications are displayed
and others (Österberg et al., 2020). (Figueiredo et al., 2018; Chauhan, 2020).
Therefore, lignin has been considered as a new potential feedstock In addition to publications in journals, several patents have already
for the production of eco-friendly nanoparticles (Liu et al., 2019a). The been filed, demanding methods of synthesis and application of LNPs.
simple fact of extracting lignin in the extraction of lignin in the kraft Dirk et al. (2015), patented a method of synthesis of LNPs (US 9,102,801
process brings advantages to minimize global warming, since it was B1) from lignosulfonate, with a size smaller than 40 nm, as well as the
calculated a reduction of up to 17% in the emission of kg CO2eq per air mixture of these nanoparticles to a polymeric matrix. The method con
dry metric ton (Culbertson et al., 2016). With the advent of LNPs syn sisted of mechanically decreasing the size of the lignin and, before or
thesis, the term “green tool” has been used a lot, mainly due to the fact during this process, exposing the lignin particles to the precursor dia
that synthetic materials can be replaced by alternative renewable ma zonium, increasing the solubilization of the lignin in organic solvents.
terials, in this case, the lignin present in plant biomass. However, this Liu et al. (2014) also patented a method of producing LNPs and appli
analysis needs to be done in more depth, and the entire LNP production cation (CA2930604C), in which lignin is solubilized in an alkaline me
process needs to be taken into account. Recent studies in this area have dium with water and, subsequently, the solution is heated (50–120 ◦ C)
shown that the synthesis of LNPs is complying with the principles of until formation of LNPs. The application of the patented LNPs, among
green chemistry, since production methods are less environmental several claims, boils down to incorporation into a polymeric complex
hazardous. (heterocyclic), water-rinse-resistant and with antimicrobial, UV-
The feasibility of producing LNPs depends on the possibility of scale- protection, anti-oxidation, anti-soiling characteristics. Among the
up, manufacturing cost and applications. A techno-economic assessment claims of numerous other patents, is the use of LNPs as surfactants
carried out by Assis et al. (2018) about Lignin Micro- and Nanoparticles (CA2930604C, Liu et al., 2014), hydrophobization of material when
(LMNPs), evaluated the main factors involved: the cost of lignin and the added to polymeric matrices for biomedical and pharmaceutical pur
synthesis of nanoparticles (manufacturing costs), utilities, and depreci poses (BR-4784-3 A21, Arantes and Marotti, 2018), as biomaterial for
ation. The authors report that it is possible to produce LMNPs in the agricultural drug carrier (AU2017214451 A1, Wurm et al., 2017),
range of 870–1170 USD/t, with sales prices ranging between 1240 and among others.
1560 USD/t. Also, using a high concentration of lignin, it is possible to In this review article, we attempt to summarize the recent de
reduce the price of LMNPs production below 600 USD/t. velopments in lignin nanoparticles, providing a comprehensive, critical,
Biodegradability is another key feature of LNPs. Although studies on and accessible overview and background information about this inno
the biodegradability of LNPs are still lacking, as it is a natural vative technology and trending topic in sustainability. Therefore, we
biopolymer and considering the ability of fungi and bacteria to degrade report the ongoing activities in the field of LNPs, compiling the largest
lignin by laccase and peroxidase enzymes (Salvachúa et al., 2016; number of papers and current researchers available in the literature.
Schneider et al., 2018; Schneider et al., 2019b), it is assumed that lignin- Beyond the presentation and discussion of the use of different types of
based nanoparticles can be degraded by microorganisms. And if they are lignin from different raw material to synthesize LNPs with different
not biodegradable, at least compostable (Österberg et al., 2020), since features, we also compare the variations in production methods and
most parts of biodegradability tests are currently only performed under numerous applications of LNPs. In addition, a special focus on the for
aerobic conditions (Iwata, 2015). However, more aggressive processes mation of these bionanomaterials, as well as the challenges, perspectives
of extraction and recovery of lignin and synthesis of LNPs can interfere and its indispensable need in our contemporary society.
their biodegradability.
In general, the synthesis of LNPs is a controllable and simples process 2. The formation mechanism of lignin nanoparticles
and it usually leads to the formation of uniform nanoparticles, despite
the inherent heterogeneity and complexity of lignin (Tian et al., 2017a). The LNP formation mechanism depends on the process of obtaining
In addition, LNPs increase their properties, such as antioxidant activity, lignin, post-modification of extracted lignin (physical/chemical/bio
when compared to their parent biopolymer, due to their high surface- logical) or non-modification and, mainly, by the synthesis method of the
area-to-volume (Lu et al., 2012a, 2012b). nanoparticles used, including the type of solvent in which the lignin is
Previous studies have confirmed that the LNPs can be used as anti solubilized, as well as the end-point solvent concentration, and the pH
oxidants (Yearla and Padmasree, 2016; Yang et al., 2016a, 2016b; control. Lignin can be dissolved in a polar solvent that has the ability to
Trevisan and Rezende, 2020), as UV-protectant sunscreen (Wang et al., break the intermolecular or intramolecular hydrogen bonding of lignin
2019; Trevisan and Rezende, 2020), dispersants, coatings and paints molecules (Xiong et al., 2015). The LNP formation is credited to the
(Österberg et al., 2020), antimicrobials (Richter et al., 2015), a drug amphiphilic property of the lignin, which comprises a hydrophobic
carrier system (Figueiredo et al., 2017a), for gene delivery (Ten et al., group (phenylpropanoid units) and a hydrophilic part (hydroxyl and
2014), for encapsulating hydrophobic molecules (Tortora et al., 2014; carboxyl groups) (Fig. 3). Both play important roles in forming LNPs.
Dai et al., 2017), for tissue engineering (Kai et al., 2016b), for hybrid There is still no consensus regarding the mechanism for forming LNPs.
nanocomposites (Gupta et al., 2015; Chen et al., 2019), as biocatalysts But, basically, the hydrophobic part of lignin may self-assemble as the
(Sipponen et al., 2018a), as an agricultural biocide delivery system core in the formation of LNPs while the hydrophilic part turns towards
(Zikeli et al., 2020), for immobilising enzymes (Dong et al., 2019), for their surface. When lignin solution is added into water and vice-versa,
dye removal (Azimvand et al., 2018a), for food packaging (Yang et al., after being dissolved in a polar organic solvent, formation of LNPs will
2016b), for wound dressing (Reesi et al., 2018), as supercapacitors (Yu take place in a hydrophilic aggregation by non-covalent interactions,
et al., 2018), as a nano-trap for flocculation (Yin et al., 2018) and for such as H-bonds with hydroxyl groups in the surface (Tian et al., 2017a;
adsorbing heavy metals (Xiao et al., 2019), among many others appli Zhang et al., 1997). Thus, lignin tends to organize itself into spherical
cations (Fig. 2). nanoparticles that minimize the surface area in contact with the non-
The first report of LNPs is from Frangville et al. (2012) who devel solvent phase (normally water) (Österberg et al., 2020).
oped two different methods of synthesising non-toxic and biodegradable It is suggested that the hydrophobic effect might be related to other
LNPs from a commercial lignin (Indulin AT). The first one, through non-covalent interactions, such as van der Waals forces and π–π stacking
dialysis, solubilizing lignin in ethylene glycol and subsequent precipi (Qian et al., 2014a). Lignin have a tendency to form aggregates through
tation with HCl to form LNPs with sizes ranging from 100 nm to a the π–π interaction of the aromatic rings and molecular aggregation by
4
Fig. 3. A schematic proposal for the formation of LNPs (adapted from Tian et al., 2017a, 2017b). Lignin, a molecule with an amphiphilic character, can be dissolved
in a polar solvent, resulting in breaking the hydrogen bonding between its molecules. With the addition of an antisolvent, such as water, the lignin molecules begin to
aggregate, increasing the aromatic π-π interactions among each other (inside the lignin molecule) and decreasing the overall interface area where hydroxyl and
carboxyl groups form effective H-bonds with water molecules.
the van der Waals interaction in organic solvents (Xiong et al., 2017a; Österberg et al., 2020).
Deng et al., 2011; Sarkanen et al., 1982). The non-covalent π–π in Although there is a lack of studies regarding the control of pH in the
teractions between the phenyl rings decrease in the order S > G > H synthesis of LNPs, what has already been seen is that it is possible to
units (Ma et al., 2020). Therefore, hardwoods and herbaceous are ideal decrease the size of the nanoparticles, gradually increasing the pH, from
feedstocks for the formation of LNPs, considering the greater number of 3 to 6 (Leskinen et al., 2017), what is expected, since LNPs, in addition to
methoxy groups of aromatic ring in the lignin S unit and π–π in phenolic groups, have carboxylic acid groups on their surface and their
teractions, since lignin S units are predominant in these plant species. deprotonation ends up increasing the surface charge and electrically
In the process of transforming raw lignin into LNPs, there is a shift in stabilizing the LNPs (Österberg et al., 2020).
UV-absorption wavelength (increasing to 280 nm) resulting from A schematic representation for the formation of LNPs is presented in
lowering the energy level of the excited electrons by π-stacking (Chen Fig. 3, following the self-assembly principle in a micellization process.
et al., 2018). Moreover, the lignin molecules tend to grow into a However, some studies show a difference between the conformation
spherical shape, thus decreasing its surface energy (Jin et al., 2001). nature of LNPs according to the hydrophilic/hydrophobic behaviour of
In some cases, lignin needs to undergo chemical modification to form the lignin molecule, as proposed by Qian et al. (2015) and Xiong et al.
nanoparticles by enhancing the hydrophobicity of the starting lignin (2015). These different conformations are related to the possible ways of
material for a resulting smaller particle size, better regular shape and extracting lignin and post-extraction methods of modifying the
higher stability (Tian et al., 2017a; Qian et al., 2014a; Zhao et al., 2016). molecule.
Qian et al. (2014a) reported that alkali lignin needs to be acetylated due
to the large amount of phenolic hydroxy groups present in alkali lignin 3. LNPs characteristics
which, due to electrostatic repulsion, do not allow the formation of
dense packing in sphere-shaped nanoparticles and the increase in LNPs are typically characterized by different shapes (Fig. 4, Table 1).
hydrogen bonding between lignin and water makes it difficult the The shape can vary from well-defined spheres, isolated (Xiong et al.,
colloid formation. Therefore, π–π interaction is related to the formation 2017a) or in structures such as clusters (Kai et al., 2015b) and aggre
of nanoparticles after lignin acetylation. gates (Yang et al., 2019a, 2019b), hollow spheres (Xiong et al., 2017b),
There is still a lack of information to understand the chemistry and quasi-spheres (Myint et al., 2016), cuboids (Saratale et al., 2019), non-
driving forces that lead to the formation and stabilization of LNPs. spherical (Chen et al., 2019) or irregular shape (Gilca et al., 2015). In
Overcoming this hurdle, it will help in understanding how LNPs can be addition, higher lignin concentrations commonly allow higher LNPs
applied to different areas, for example, in the controlled release of drugs production yields (Chen et al., 2018).
and the behaviour of these nanoparticles in target tissues (Sipponen The synthesis of LNPs, as well as their morphology, are also closely
et al., 2018b). Recently, Zhao et al. (2017) studied the formation of related to the different motifs with different connections that are present
lignin aggregates and established that this degree of aggregation occurs in lignin. The gap between the bonds can also determine the morphology
through competition between electronic interactions, mainly via the and size of the LNPs. The molecular weight of lignin is another pre
aromatic moieties, and repulsion force and intermolecular H-bonds. dominant factor. Dissolving lignin in solvents that break certain bonds
Sipponen et al. (2018b) developed a study to understand the lignin ag between aromatic rings, can result in lignin of lower molecular weights
gregation process. According to the authors, the formation of LNPs and, consequently, in smaller particles (Österberg et al., 2020).
dependent on the concentration of ethanol (solvent) in the ethanol- Several factors affect the stability and storage in LNPs, such as
water mixture, on the addition of water (anti-solvent) in the system temperature, pH, ionic strength, exposure to light, salt concentration.
and on the molecular size of the lignin fragments. Therefore, with the Regarding storage, it was found that LNPs are stable at room tempera
progressive addition of water, lignin self-assembles and begins to pre ture or at 4 ◦ C, with ionic strength lower than 0.01, in a wide pH range
cipitate in nanoparticles, from high to low molecular weight, following a (5–11) and, when added in emulsions, they maintain their stability at
kinetically controlled nucleation− growth mechanism. low salt concentrations (Trevisan and Rezende, 2020). Good stability of
Furthermore, LNPs tend to form aggregates in higher concentrations LNPs, without changes in their morphological properties, size and sur
of lignin that did not result in stable colloidal dispersions. Instead, the face charge, can vary after a few weeks of storage (Frangville et al.,
particles form interlinked networks resulting in known aggregates and/ 2012) up to 6 months (Figueiredo et al., 2017a).
or clusters. As the concentration of the solvent decreases and the amount The morphology of LNPs is of great importance in their performance.
of water becomes smaller, the formation of aggregate nuclei decreases For example, amorphous lignin and LNPs with more irregular mor
and particles with a smaller size appear (Sipponen et al., 2018a, 2018b; phologies, with sharp edges, can impair their interaction with other
5
Fig. 4. Representation of the different shapes of LNPs. The shapes that these nanoparticles have are directly related to the type of lignin used (extraction method),
whether it has undergone chemical/physical/biological modifications and the method of production of the LNPs.
materials, as in the development of hybrid nanocomposites. LNPs with are essential. On the other hand, in the field of cosmetics formulation,
more spherical morphologies can be ideal for Pickering stabilization and delivery systems and other biomedical applications, radical decrease in
biological applications, as they are excellent carriers of hydrophobic absorbance of 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) tests are
substances in target cells, in addition to smaller particles being less performed, in addition to absorbance and transmittance in UV-
cytotoxic when compared to macro particles (Sipponen et al., 2018b; spectrometer. More specifically, in vitro and in vivo toxicity tests are
Österberg et al., 2020). required in specific cases, such as drug delivery for the treatment of
Size also has a very variable range that depends directly on the raw cancer cells. In addition, whenever these LNPs are modified or used in
material, the form of lignin extraction and, mainly, the method of pre combination with other materials, cytotoxicity tests must be repeated
paring the nanoparticles (Table 1). It can range from 1 to more than 200 and evaluated, proving their safety.
nm, reaching micro sizes. The size of the nanoparticles to be synthesized
and, consequently, the method employed will depend on their applica 4. LNP preparation methods
tion purpose. For example, nanoparticles to be applied in drug delivery
for cancer treatment should preferably have a size between 70 and 250 With the growing research in green nano-biotechnologies, several
nm, because the neovascular development induced by tumor growth is methods have been developed for preparing LNPs, using different
characterized by and endothelium with size range of 200–780 nm chemical, physical and biological approaches. These methods include
(Gaumet et al., 2008; Figueiredo et al., 2017a). On the other hand, antisolvent precipitation (Frangville et al., 2012), solvent exchange, also
nanoparticles used in hybrid nanocomposites, such as in hydrogels known as solvent shifting (Lievonen et al., 2016), ultrasonication (Kim
(Chen et al., 2019), films (Yang et al., 2016a), fibres (Kai et al., 2015a) or et al., 2013), interfacial crosslinking (Yiamsawas et al., 2014), poly
in Pickering emulsions (Qian et al., 2014b), do not necessarily need to merization (Jiang et al., 2013), biological methods (Rangan et al., 2017)
have such small sizes since they are used for more macro applications and others (Fig. 5).
and, in addition, interact with larger size compounds. The lignin nanomaterials can have different morphologies, called by
The LNPs are characterized by their average particle size (Z- the authors nanoparticles (Figueiredo et al., 2017a), nanospheres (Sip
average); heterogeneity of nanoparticles based on their size, called ponen et al., 2018a), nanotubes (Ten et al., 2014), nanofibers (Kai et al.,
Polydispersity Index (PDI); average zeta (ζ)-potential (surface charge); 2017), nanocapsules (Chen et al., 2016), nanomicelles (Li et al., 2017),
Static Light Scattering (SLS), that measures the intensity of the scattered nanofilms (Farooq et al., 2019) and others.
light to obtain the average molecular weight; Dynamic Light Scattering The most common method to produce LNPs is via a solution-based
(DLS), that measures the mean of hydrodynamic diameter; and images micellization process, following the self-assembling principle, where
of the shape and morphology of LNPs obtained by Scanning Electron the lignin needs to be first dissolved in some organic solvent and, after
Microscope (SEM), Field Emission Scanning Electron Microscope that, the nanoparticles will be formed with the addition of an antisolvent
(FESEM), Transmission Electron Microscope (TEM), Atomic Force Mi (usually water) or during a dialysis process (also in water) (Tian et al.,
croscopy (AFM) and crystallographic structure by X-ray Diffraction (X- 2017a;Qian et al., 2014a). These and other methods of producing LNPs
RD). will be described in more detail below.
According to the application that is intended to be given to LNPs, the
respective characterization techniques are employed. In the area of 4.1. Antisolvent precipitation
development of hybrid nanocomposites and tissue engineering, analyses
of X-ray Photoelectron Spectroscopy (XPS), Fourier-transform Infrared This was the first method developed for producing LNPs. It was
(FT-IR) spectroscopy, Differential scanning calorimetry (DSC), Ther initially proposed by Frangville et al. (2012) who introduced the
mogravimetric analysis (TGA) and Thermo-mechanical analysis (TMA) “standard methods” of LNPs precipitation. The authors used ethylene
6
W.D.H. Schneider et al.
Table 1
Summary of different methods used in the preparation of LNPs and other lignin-based nanomaterials, the morphology, size, yield and shape of the nanomaterials synthesized as well as their potential applications.
Morphology Raw material Method Size (nm) Yield (%) Shape Application Reference
Antisolvent precipitation
Nanoparticles Low-sulfonate lignin Antisolvent precipitation (ethylene glycol) > 100–1200 NRa Non-spherical Possible applications in foam, emulsion Frangville et al. (2012)
(Indulin® AT, Iot MB05, IAT) + Acid precipitation (HCl) clusters stabilizers and drug delivery system
Antisolvent precipitation (NaoH) + Acid
precipitation (HNO3)
Nanoparticles Organosolv poplar lignin Antisolvent precipitation (acetone + CO2) ~144 NR Spheres Antioxidant activity, food processing and Lu et al. (2012a,
pharmaceutical industries 2012b)
Nanoparticles Protobind 1000 lignin Antisolvent precipitation (ethylene glycol) 50–150 NR Clusters/ NR Gupta et al. (2014)
+ Acid precipitation (HCl) Aggregates
Nanoparticles Alkali lignin Antisolvent precipitation (THFb + water) ~110 NR Spheres Drug delivery systems, encapsulation of Qian et al. (2014a)
pesticides for controlling release
Nanoparticles Wheat alkali lignin Antisolvent precipitation (THF + water) 90 NR Spheres Whitening of acetylated lignin without the Qian et al. (2014c)
use of reactive mediators
Nanoparticles Lignin protobind-1000 Antisolvent precipitation (ethylene glycol) ~181 NR Cluster/Aggregates Hybrid nanocomposite with good mechanical Gupta et al. (2015)
+ Acid precipitation (HCl) and termal properties
Nanoparticles Acid acetic lignin Antisolvent precipitation 150–905 22.3–70.7 Spheres in NR Kai et al. (2015)
aggregate-like
clusters
Nanoparticles Kraft lignin Antisolvent precipitation (DMFc + CO2) ~38 90 Aggregated/ High UV-absorbing with potential for Myint et al. (2016)
Coalesced quasi- cosmetics, health and drug delivery systems
spheres
Nanoparticles/ Alkali lignin Antisolvent precipitation in (dioxane/ ~120 NR Spheres UV-blocking additive for termoplastics Qian et al. (2015)
Micelles cyclohexane)
Nanoparticles Kraft Lignin (Indulin AT) Antisolvent precipitation (ethylene glycol) 40–70 NR Non-spherical Silver-infused lignin nanoparticles with Richter et al. (2015)
+ Acid precipitation (HCl) + LNPs cores clusters antimicrobial effects
infused with Silver
7
Nanoparticles Pristine lignin from Arundo Antisolvent precipitation (ethylene glycol) ~48 (40–60) NR Spheres As a nanofiller in bio-based matrices Yang et al. (2015a)
donax L. +Acid precipitation (HCl)
Nanoparticles Pristine lignin from Arundo Antisolvent precipitation (ethylene glycol) 20–80 NR Clusters As a biofilm in food packaging application Yang et al. (2015b)
donax + Acid precipitation (HCl)
Nanocapsules Kraft lignin Antisolvent precipitation (ethanol + water) ~200–300 NR Hollow spheres NR Li et al. (2016)
nanocapsules
Nanoparticles Kraft lignin and organosolv Antisolvent precipitation (ethylene glycol) 45–250 NR Spheres Potential application at extreme temperature Richter et al. (2016)
+ Acid precipitation (HCl)
Nanoparticles Pristine lignin from Arundo Antisolvent precipitation (ethylene glycol) NR NR Films Antioxidant and antibacterial, potential Yang et al. (2016a)
donax L. + Acid precipitation (HCl) against bacterial, plant/fruit pathogens in
food packing
Nanoparticles Hardwood dioxane lignin (DL) Antisolvent precipitation (acetone + water) 80–104 63 (DL) 33 Spheres Antioxidant and UV-protectant activity Yearla and Padmasree
and Softwood alkali lignin (AL) (2016)
(AL)
Nanoparticles Alkali lignin Antisolvent precipitation ~130 68.2 Spheres Delivery of hydrophobic drugs (resveratrol) Dai et al. (2017)
Nanomicelles Alkalin lignin Antisolvent precipitation (ethanol + water) 45–110 80.27 Spheres Controlled and pH responsive delivery of Li et al. (2017)
anticancer drugs

Nanoparticles Steam-pretreated Poplar Antisolvent precitation (DMSOd + dialysis 131 (POP) 90,9 (POP) Spheres NR Tian et al. (2017a)
(POP), Lodgepole Pine (LPP) in water) 104 (LPP) 41 (LPP)
and Corn Stover (CS) 218 (CS) 81,8 (CS)
Nanoparticles Alkali lignin Antisolvent precipitation (ethylene glycol) 40–60 NR Uniform and flat Removal of Safranin-O dye and Basic Red 2 Azimvand et al.
+Acid precipitation (HCl) dye (2018a)
Nanoparticles Alkaline lignin Antisolvent precipitation (APSe + water) 80–230 Higher Quasi-spheres and Drug delivery carrier for hydrophobic Chen et al. (2018)
yields aggregates compounds
Nanofilms/ Softwood Kraft lignin (BioPiva Antisolvent precipitation (acetone + water) 102 88 Spheres Waterproof cellulose nanofibril composite Farooq et al. (2019)
Nanoparticles 100) films
Nanoparticles Steam exploded rice straw Antisolvent precipitation (ethylene glycol) 15–20 Higher Spheres Act as a anticorrosive nanofillers Rahman et al. (2018)
lignin +Acid precipitation (HCl) yields
(continued on next page)
Table 1 (continued )
Nanoparticles Pristine lignin from Arundo Antisolvent precipitation (ethylene glycol) 40–60 ~78–88 NR Antioxidant and antibacterial activity Yang et al. (2018a)
donax + Acid precipitation (HCl, H2SO4, H3PO4)
Nanoparticles Alkali lignin Antisolvent precipitation (ethylene glycol) 32–120 NR Spheres Antioxidant and antibacterial properties Yang et al. (2018b)
+ Acid precipitation (HCl)
Nanoparticles Pristine lignin (Arundo donax Antisolvent precipitation (ethylene glycol) 32.5–65.1 NR Spheres Nanocomposite with potenital for Yang et al. (2018c)
L.) + Acid precipitation (HCl) automative, flooring, acrylic glasses and
lenses
Nanoparticles Acid-alkali corn biomass Antisolvent precipitation (acetone + water) 26–88 92.9 Clusters spheres NR Camargos et al. (2019)
Nanoparticles Alkali lignin Antisolvent precipitation (DMF + water) 121–140 NR Spheres Chromium (III) removal Dai et al. (2019)
Nanoparticles Alkali lignin Antisolvent precipitation (ethylene glycol) 60–80 NR Irregular shape and Antioxidant nanocomposite He et al. (2019)
+ Acid precipitation (HCl) aggregates
Nanoparticles Corn stover organosolv lignin Antisolvent precipitation 132–1099 62,6–78.8 Spheres Application in biorefineries Liu et al. (2019b)
Nanoparticles Sulfur-free alkaline lignin Antisolvent precipitation (acetone + water) ~110 NR Aggregates/ UV-blocking films through core-shell-lignin- Xing et al. (2019)
Spheres melanin nanoparticles in PBATf for potential
application in agricultural or food packing
Nanoparticles Kraft lignin Antisolvent precipitation (ethylene glycol) 30–152 NR Aggregates NR Yang et al. (2019a,
+Acid precipitation (HCl) 2019b)
Nanoparticles Iroko sawdust and Norway Antisolvent precipitation (DMSO + water) 150–320 NR Flaky and crusty Wood-protection applications against Zikeli et al. (2019)
spruce aggregates weathering
Nanoparticles Softwood kraft lignin Antisolvent precipitation (DMF + water) 200–500 NR Colloidal particles Cholesterol-modified lignin nanoparticle for Pourmoazzen et al.
drug delivery (acid folic) (2020)
Nanoparticles Acid-alkali elephant grass Antisolvent precipitation (acetone + water) >100–500 37 Hollow spheres Cream lotions and tinted sunscreens Trevisan and Rezende
lignin (Pennisetum purpureum) (2020)
Nanocapsules/ Beach wood sawdust (Fagus Antisolvent precipitation (DMSO + water) ~108 NR Spheres and Biocide delivery system for wood Zikeli et al. (2020)
nanoparticles sylvatica L.) clusters preservation
Solvent Exchange/Solvent shifting

8
Nanoparticles Kraft lignin (LignoBoost) Solvent exchange (THF + dialysis in water) 200–500 NR Spheres NR. Lievonen et al. (2016)
Nanoparticles Softwood kraft lignin Solvent exchange 10–30 and 50–400 NR Spheres and hollow Material with magnetic, antibacterial and Lintinen et al. (2016)
(LignoBoost™) nanoparticles catalytic properties
Nanoparticles Softwood kraft lignin Solvent exchange (THF + dialysis in water) 221 (LNPs) NR Spheres Drug delivery and enhanced antiproliferation Figueiredo et al.
(LignoBoost™) 160 (Fe-LNPs) effect in cancer cells (2017a)
464 (Fe3O4-LNPs)
Nanoparticles LignoBoost™ softwood kraft Solvent exchange (THF + dialysis in water) 218–262 NR Spheres Target and pH responsive delivery of Figueiredo et al.
lignin anticancer drugs (2017b)
Nanoparticles Kraft lignin (Lignoboost®) Solvent exchange ~259 85 Spheres Stabilization of durable Pickering emulsions Sipponen et al. (2017)
Nanoparticles Steam treated Solvent exchange (DMSO + dialysis in ~195 NR Spheres Nanocomposite with high UV-shielding Tian et al. (2017b)
hardwoodpoplar water) efficacy, antioxidant activity and in
packaging field
Nanoparticles Enzymatic hydrolysis lignin Solvent exchange (THF + dialysis in water) 190–590 72.15 Spheres NR Xiong et al. (2017a)
Nanoparticles Enzymatic hydrolysis lignin Solvent exchange (THF + dialysis in water) 419–566 ~70 Hollow shperes NR Xiong et al. (2017b)
Nanoparticles Alkali (AL) and Organosolv Solvent exchange (DMSO + dialysis in 115–300 NR Spheres Pickering emulsions stabilizers for bioactive Bertolo et al. (2019)
(OGS) lignin from sugarcane water) (AL) compounds encapsulantion (curumin)
bagasse 270–680 (OGS)

Nanoparticles LignoBoost lignin Solvent Exchange (flow tubular reactor) 200–400 95 Spheres NR Ashok et al. (2020)
Ultrasonication
Nanoparticles Sulfonate lignin from Ultrasonication ~230 NR NR Antibacterial effect, drug delivery Kim et al. (2013)
hardwood
Microcapsules Kraft lignin Ultrasonication 100–1100 NR Spheres Delivery of hydrophobic molecules Tortora et al. (2014)
Nanoparticles Wheat straw lignin Ultrasonication 100–500 NR Irregular shape NR Gilca et al. (2015)
Nanoparticles Softwood kraft lignin (Indulin Ultrasonication 10–50 NR Irregular Bioderived fillers for advanced Gonzalez et al. (2017)
AT) nanocomposite applications
Nanoparticles Alkali lignin Ultrasonication ~200 NR Non-spherical Nanocomposite hydrogel with potential use Chen et al. (2019)
in tissue engineering, regeneration, artificial
muscles, Strong underwater antifouling

materials
Nanoparticles Lignin from giant reeds Ultrasonication 10–50 NR Irregular shape Nanocomposite hydrogel for drug delivery, Ingtipi and Moholkar
(Arundo donax) food packaging and wound dressing (2019)
Interfacial crosslinking
Nanocapsules Sodium lignosulfonate Interfacial crosslinking 311–390 50 Hollow Potential nanocontainers for agricultural Yiamsawas et al.
(water) nanocapsules applications (2014)
162–220
(cyclohexane)
Nanoparticles Kraft lignin Interfacial crosslinking 90–1000 NR Spheres Surfactant for Pickering emulsions Nypelo et al., 2015
Nanocapsules Sodium lignosulfonate Interfacial crosslinking 100–200 NR Spheres Drug delivery and controlled release os Chen et al. (2016)
nanocapsules hydrophobic compounds
Nanoparticles Organosolv Acacia lignin Interfacial crosslinking (lignin + AgNO3) 10–50 NR Spheres Ag-LNPs with Antibacterial activity Aadil et al. (2019)
Nanoparticles Lignin from wheat straw Interfacial crosslinking (AgNO3 solution + 15–20 NR Cuboidal Ag-LNPs as antioxidant, antimicrobial and Saratale et al. (2019)
lignin in wather bath at 50 ◦ C for 60 min) anticancer activity
Nanoparticles Formic acid bamboo lignin Interfacial crosslinking (ECHg) + 10–20 NR Spheres/ Magnetic nanoparticles for ultrafast Zhang et al. (2019)
(Neosinocalamus affinis) ultrasonication Aggregates adsorption of heavy metal ions
Polymerization
Nanoparticles Sulfate lignin Polymerization >100 NR Colloidal Nanocomposite with natural rubber Jiang et al. (2013)
Nanoparticles Alkali lignin Polymerization 237–404 NR Spheres Surfactant por Pickering emulsion Qian et al. (2014b)
Nanotubes - Sorgum (Sorghum bicolor) Polymerization 10–18 (length) NR Different lengths Gene delivery Ten et al. (2014)
- Sorgum with BTx623-bmr6 172–223 and wall thickness
mutation (diameter)
- Pine (Pinus taeda)
- Poplar (Poplus deltoides)
- Sugar cane bagasse
9
(Saccharum spp.)
Nanofibers Kraft lignin Polymerization 362–623 NR Nanofibers Good interaction and proliferation of human Kai et al. (2015a,
dermal fibroblasts 2015b)
Nanoparticles Kraft lignin Polymerization 100–200 NR Polyplexes Gene delivery system Liu et al. (2015)
nanoparticles
Nanofibers Alkali lignin Polymerization ~350 NR Nanofibers Nanocomposite with antioxidant activity and Kai et al. (2016a)
potential in tissue engineering scaffolds
Nanoparticles Kraft lignin Polymerization (RAFTh) 5–12 NR Spheres Pickering emulsions Silmore et al. (2016)
Nanofibers Alkali lignin Polymerization 300–500 51–68 Nanofibers Antioxidant activity and potential in tissue Kai et al. (2017)
engineering scaffolds
Nanoparticles Alkaline lignin Polymerization (Inverse-emulsion) ~160 71.15 Irregular shape Nano-trap for heavy metal ion capture and Xiao et al. (2019)
bacterial inhibition
Biological methods
Nanoparticles Soda coconut fibres Microbial hydroliysis 22–207 58.4 Non-spherical Useful in textile, biomedical and Juikar and
environmental applications Vigneshwaran (2017)
Nanoparticles Indian ridge gourd (Luffa Enzymatic hydrolysis 20–100 NR Cuboidal Potential in automobile, pharmaceutical and Rangan et al. (2017)

cylindrica) polymers
Combined methods
Nanoparticles Alkaline Sarkanda grass lignin Hydroxymethylation + Acid precipitation 50–1000 NR NR NR Gilca et al. (2015)
(HCl)
Nanoparticles Agave tequilana soda (SOD) Crosslinking + alkaline precipitation 400–1400 (SOD) NR Spheres Skin photoprotection Gutiérrez-Hernandez
and organosolv (OGS) lignin 1200–3800 (OGS) et al. (2016)
Nanoparticles Softwood kraft lignin Solvent exchange (THF + dialysis) + ~200 NR Colloidal particles Biomaterial applications (medicine, foods Mattinen et al. (2018)
(LignoBoost™) Enzymatic modification + Chemical and cosmetics)
oxidation of LNPs (H2O2 via ultrasonication)
Nanospheres Pine kraft lignin Solvent exchange + Enzyme modification ~177 NR Clusters and Biocatalytic ester synthesis in aqueous media Sipponen et al. (2018a)
spheres
Nanoparticles Switchgrass klason lignin Ultrasonication assisted by alkali method ~220 NR Spheres LNPs-gelatin complex as a flocculant for the Yin et al. (2018)
capture of Staphylococcus aureus and
Escherichia coli
Nanoparticles Corn stover and switchgrass Antisolvent precipitation (acetone + water) 142–234 75–87 Spheres Biorefineries Liu et al. (2019a)
+ ultrasonication
Nanoparticles Alkalin corn cob lignina Solvent exchange (THF) + Ultrasonication 100–800 82.3 Spheres Sunscreen elaboration Wang et al. (2019)
Nanoparticles Wheat straw Solvent exchange and pH shifting NR NR NR Life cycle assessment Koch et al. (2020)
Other methods
Nanoparticles Alkaline wheat straw and Hydroxymethylation precipitation + 50–500 NR Biocide properties Popa et al. (2011)
sarkand grass epoxydation
Nanoparticles Calcium softwood NR 1600 NR Nanoparticle- Nanocomposite used as a reinforcing agente Del Saz-Orozco et al.
lignosulfonates reinforced foams or filler in phenolic composites (2012)
Nanoparticles Protobind 2400 lignin Freeze-drying and stabilization 25–150 ~58% Porous NR Gonugunta et al.
nanostructures (2012)
Nanofibers Softwood kraf lignin Electrospinning 61–500 NR Amorphus Defect-free electrospun fibres Ago et al. (2013)
nanofibers
Nanoparticles Kraft (KL) and lignosulfonate Heating in water (80 ◦ C, 3 h) 8–14 (KL) 16–20 NR Spheres Catalyst for cross-coupling reactions in water Coccia et al. (2013)
lignin (LSL) (LSL)
Nanoparticles Softwood kraft black liquor Mechanical shearing <100 NR Irregular shape Potential to be used in PVAi, increasing the Nair et al. (2014)
thermal stability of nanolignin/PVA blends
Nanoparticles Kraft, alkali and organosolv Aerosol flow reactor 230–1900 > 60 Spheres Surfactant free-emulsification Ago et al. (2016)
lignin
10
Nanoparticles Alkali lignin Heating and mechanical agitation 10–15 98 Spheres Antibacterial, antifungal, antioxidant and Marulasiddeshwara
antiplatelet activity et al. (2017)
Nanoparticles Alkali lignin Aerosol assisted self-assembly 98–133 NR Hollow/Solid Sunscreen cosmetics and drug delivery Mishra and Wimmer
colloidal applications (2017)
nanoparticles
Nanofibers Lignin nanofiber aqueous gel Grinding method 100–250 NR Uniform Wound-healing Reesi et al. (2018)
nanofibrous based
j
Nanoparticles Lignosulfonate lignin Alkaline precipitation (LSQA precipitated NR 75.51 NR Immobilization and desorption of celulase Dong et al. (2019)
with Fe3O4 in amonia solution)
a
NR: Not reported.
b
THF: Tetrahydrofuran.
c
MF: Dimethylformamide.
d
MSO: Dimethyl sulfoxide.
e
APS: Aqueous sodium p-toluenesulfonate (pTsONa) solution.
f
PBAT: Poly(butylene adipate-co-terephthalate).
g
ECH: Epichlorohydrin.

h
RAFT: Reversible addition–fragmentation chain transfer.
i
PVA: Polyvinyl alcohol.
j
LSQA: Quaternized lignosulfonate lignin.
Fig. 5. LNPs preparation methods. Different methods of producing LNPs have already been developed, involving chemical, physical, and/or biological techniques,
resulting in different shapes of LNPs, sizes, yields and economic and environmental impacts. Illustration adapted from Figueiredo et al. (2017a, 2017b) and Liu and
Chung (2017). *Note. The crosslinking is not a proper method of producing LNPs. It consists of a method of stabilizing colloids during their formation, generating
particles and capsules.
glycol as a solvent to dissolve lignin and hydrochloric acid to precipitate dangerous for the environment when precipitation with acid is used,
NPLs. In other methods adapted from Frangville et al. (2012), different most of them can be recovered, minimizing the disadvantages of this
solvents and anti-solvents were used. For example, Yearla and Pad method which, as an advantage, provides the formation of nanoparticles
masree (2016) used an acetone solution (9:1, v/v) as a solvent and with well-defined morphology, shape and stability.
deionized water as an anti-solvent to promote the precipitation of
nanoparticles. Water is generally used as an antisolvent, due to the low
4.2. Solvent exchange/solvent shifting
solubility of lignin in water. As solvents, in addition to acetone, tetra
hydrofuran (THF) (Figueiredo et al., 2017a), dimethylsulfoxide (DMSO)
This method consists of a dual system of solvents, one of which is an
(Tian et al., 2017a), dimethylformamide (DMF) (Dai et al., 2019) and
organic solvent and the other is water, which is in excess, being that
aqueous sodium p-toluenesulfonate (APS) (Chen et al., 2018) are used.
LNPs are formed due to their decreasing solubility (Wurm and Weiss,
As an antisolvent, Lu et al. (2012a, 2012b) used supercritical CO2 to
2014; Beisl et al., 2017). Lievonen et al. (2016) were one of the first to
carry away acetone used for dissolving organosolv lignin. Myint et al.
describe the solvent exchange method, based on the anti-solvent pre
(2016) produced LNPs using a compressed fluid anti-solvent (clCO2)
cipitation method by Frangville et al. (2012). Similar to the method
method. It is important to highlight that in many LNP synthesis studies, a
described earlier, solvent exchange/shifting uses a solvent to dissolve
pH change is used to precipitate nanoparticles, a method known as pH
the lignin and an anti-solvent, normally water, due to lignin’s water-
shifting. This is what Frangville et al. (2012) proposed in their pioneering
insoluble characteristic at neutral pH, as opposed to the anti-solvent
methods of producing LNPs. The LNPs were also precipitated by
precipitation method, in which excess water or pH shifting is used to
decreasing the pH value using HNO3 after lignin was dissolved in water
precipitate the nanoparticles. The solvent exchange/shifting method
(pH 12) set with NaOH. Richter et al. (2015), in a similar way, precip
shows a simple system in which the lignin-solvent solution is directly
itated lignin from an aqueous NaOH solution at pH 12 by dropping the
introduced into a dialysis bag (immersed in water) and the LNPs are
pH value with HNO3. Despite using a solvent in the preparation of these
formed during the dialysis process. Studies involving synthesising LNPs
nanoparticles, which makes the process more expensive and even more
through solvent exchange/shifting include those performed by Lintinen
11
et al. (2016), in which the condensation reaction of iron isopropoxide copolymers and nanoparticles by atom transfer radical polymerization
with lignin in THF solution and further hydrolysis and dialysis in water (ATRP), via grafting lignin onto 2-(dimethylamino)ethyl methacrylate
was carried out, and a work by Figueiredo et al. (2017a) that dialyzed a (PDMAEMA) and 2-(diethylamino)ethyl methacrylate (PDEAEMA),
mixture concentration (50:50 w/w) of lignin solution and oleic acid- respectively, starting from lignin-based macroinitiators. Kai et al.
coated Fe3O4 nanoparticles, against deionized water. Despite the (2015a) also grafted of poly(methyl methacrylate) with lignin by ATRP
advantage of being a simpler method of production, the solvent ex to produce nanofibers.
change/shifting method adds the cost of dialysis membranes, which
ends up making the process even more costly. 4.6. Biological pathway
4.3. Ultrasonication Biological methods are the most in need of study. There are few
studies reporting this methodology, which consists of using enzymes (of
In the sonication method of producing LNPs, lignin is generally bacteria and fungi) or microorganisms in synthesising LNPs. Among the
suspended in an aqueous solution and the suspension is sonicated at few studies found in the literature, Rangan et al. (2017) described a new
different times, intensities, and temperatures. The sample resulting after method for preparing LNPs from Indian ridge gourd (Luffa cylindrica) by
sonication is dried in mild conditions (Gilca et al., 2015). Among breaking down the lignin-cellulose complex using specific enzymes,
different approaches, ultrasonication is usually considered one of the resulting in lignin-derived nanoparticles with cuboidal shape and a
greenest tools due to its easy operation, low requirements for equipment 20–100 nm average size range. In another study, Juikar and Vignesh
and harmlessness to the environment (Yin et al., 2018). As for disad waran (2017) extracted nanolignin from coconut fibres by microbial
vantages, when used alone, the micro/nanoparticles resulting from this hydrolysis, specifically by a lignin-degrading fungus Aspergillus sp. What
method usually have non-uniformity in size and broad particle size is most common to find in LNP synthesis studies is the use of enzymes to
distributions, characteristics which are very dependent on the opera modify nanoparticles, as proposed by Mattinen et al. (2018), who
tional conditions selected in the ultrasound. To overcome this hurdle, treated LNPs with high Trametes hirsuta and low Melanocarpus albomyces
Wang et al. (2019) produced LNPs by a solvent exchange method redox potential laccases to improve the colloidal stability of the particles
combined with an ultrasound-assisted process. The advantage of this in an organic solvent (THF) via surface and intraparticle crosslinking.
combined method is that LNPs were rapidly formed without dialysis and Tian et al. (2017a) generated LNPs using a combined method. After
easily separated by centrifugation; THF can be recycled and reused. enzymatically hydrolysing different biomasses, the lignin residue after
enzymatic hydrolysis was used for producing LNPs, using the solvent
4.4. Interfacial crosslinking exchange method (using DMSO as the solvent).
Interfacial crosslinking consists of a process of lignin emulsification, 4.7. Other methods

normally in an oil-in-water phase; the lignin crosslinking is enhanced by
adding a crosslinking agent (Chauhan, 2020). In fact, crosslinking is not Other less explored methods have also been published in the litera
a proper method of producing LNPs. It consists of a method of stabilizing ture. Mechanical shearing is one example, as reported by Nair et al.
colloids during their formation, generating particles and capsules. In this (2014). Despite producing nanoparticles below 100 nm, which may be
way, the production path of LNPs by crosslinking is divided into two interesting for some biomedical applications, the nanoparticles did not
stages. In this method, the lignin chains must first be induced for have a regular shape. Moreover, only a simple high shear homogenizer is
crosslinking to occur, making it amphiphilic (Figueiredo et al., 2018; needed. Another method is heating in water, as proposed by Coccia et al.
Chauhan, 2020). Therefore, lignin can be dissolved in an alkaline so (2013), which produced NPLs with a spherical shape and sizes smaller
lution (which activates OH chains) to generate the dispersed phase, and/ than 20 nm. In addition, Gonugunta et al. (2012) produced LNPs
or in a solvent with surfactant (Tween 80®, Span 80®, 1-pentanol for through a combination of freeze-drying and thermal stabilization pro
example). Then, an oil/water microemulsion must be prepared and the cesses. Ago et al. (2016) also innovated in developing LNPs, producing
lignin, already solubilized, must then be emulsified, thus creating the spheres through an aerosol flow reactor used in surfactant-free emulsifi
lignin crosslinking and a water/oil interface (Figueiredo et al., 2018; cation. The process involves a single step to continuously atomize the
Chauhan, 2020). Therefore, the second step consists of adding a cross lignin precursor solution, which forms an aerosol that then passes
linking agent, which can be toluene diisocyanate (Yiamsawas et al., through a heating tube with the aid of a nitrogen gas carrier before being
2014), epichlorohydrin (Nypelo et al., 2015) or thiol (Chen et al., 2016), collected as solid particles. Another method described in the literature is
to surround a liquid aqueous core, in most cases. Usually, the cross ice-segregation that consists of the dissolution or suspension of polymeric
linking reaction is mediated by sonification and is a method to produce and monomeric precursors in water and freezing the solution (Beisl
nanocapsules/microcapsules by emulsion. Alternately, an alkaline so et al., 2017). With the freezing of lignin, a displacement of the polymeric
lution (NaOH) is used to precipitate the nanoparticles produced by material occurs that is separated by the ice crystals and surrounded by
crosslinking, as reported by Gutiérrez-Hernandez et al. (2016). Tortora them (Gutiérrez et al., 2008). Spender et al. (2012), for example, used
et al. (2014), for example, prepared spherical micro/nanocapsules via this technique to produce nanofibers from lignin. Carbon nanofibers.
interfacial crosslinking for encapsulating hydrophobic compounds for Electrospinning appears as a method to produce fibres from polymer so
biomedical applications. The authors emulsified lignin in oil in water lutions, which are pumped through a nozzle-electrode, resulting in a
using high-intensity ultrasonic technology, causing lignin crosslinking at nanometres to micrometres size range (Beisl et al., 2017). As a by-
the water/oil interface. product of failed spinning processes, nanoparticles can be generated.
For example, lignin nanofiber reinforced with cellulose nanocrystals
4.5. Polymerization could be obtained by Ago et al. (2013) using softwood kraft lignin.
More recently, Conner et al. (2020) developed a potentially scalable
The polymerization method is very similar to crosslinking. Gener process for synthesis LNPs by recirculation flash precipitation. Basically,
ally, lignin needs to be prepared to activate functional groups. The dif the process consists of a recirculatory flow system, in which lignin is
ference is that these modified groups and/or lignin native structures will dissolved in acetone and injected in a syringe. The anti-solvent, in this
be grafted onto a surface/material that has an affinity with lignin. For case, is pumped through the loop that begins and ends at the collection
example, Ten et al. (2014) studied nanotube production by polymerising vessel, at a certain rate. Lignin is also injected into the system at a certain
lignin in a alumina membrane and dissolving the template in phosphoric rate and, at the point of meeting with water, LNPs are mixed and rapidly
acid. Liu et al. (2015) and Qian et al. (2014b) synthesized lignin synthesized. Österberg et al. (2020) also describes a method for the
12
synthesis of LNPs that involves the controlled evaporation of atomized (Aadil et al., 2019) and facile one pot green synthesis of LNPs with
droplets of lignin solution, in order to obtain lignin particles with desired antibacterial, antifungal, antioxidant and antiplatelet activities by
morphologies and sizes. After being transformed into droplets, they are heating and mechanical stirring. Novel and greener LNPs for resveratrol
suspended and carried by a carrier gas, through a heated laminar flow delivery were also produced using alkali lignin without chemical
system. modification (Dai et al., 2017). Xiong et al. (2017a) proposed a new
In some publications, it is common to see “self-assembly lignin- method to prepare LNPs rapidly without any catalyst, any dialysis and
nanoparticles production”. However, “self-assembly” refers to a gen easily separated by centrifugation, even though acetic anhydride and
eral term about how lignin nanoparticles organize and interact in the THF were required. The aerosol method is another promising straight
absence of any external direction. As best explained by Xiong et al. forward technology because LNPS produced ensuring desired size and
(2017b), self-assembly based on the spontaneous control of materials property in a simple one-step process (Beisl et al., 2017; Eerikäinen
through noncovalent interactions, with no external intervention. et al., 2003). Assis et al. (2018) already aimed at scale-up the production
Therefore, in LNPs, this expression cannot be defined exactly as a of LNPs through an aerosol/atomization method. The laboratory-scale
method because it is always accompanied by some other indirect setup an aerosol flow reactor (N2 as carrier gas) coupled to an ultra
method; that is, different methods can induce the “self-assembly” of sonic nebulizer assembly and a cyclone collector assembly, which makes
lignin nanoparticles. For example, in adding an antisolvent (Figueiredo it a single step process and results in high yields of LNPs with spherical
et al., 2017a; Trevisan and Rezende, 2020; Qian et al., 2015), in the shape and sizes desired. Biological methods face the bottlenecks of LNPs
presence of another substance, such as p-toluenesulfonate (pTsONa) yield, the cost of enzyme production and, sometimes, solvents. However,
(Chen et al., 2018) or Poly (diallyldimethylammonium chloride) it results in a completely green process (Tian et al., 2017a; Rangan et al.,
(PDADMAC) (Jiang et al., 2013), with hybrid nanoparticles in AgNO3 2017). Efforts towards the use of biological methods, such as enzymes or
(Saratale et al., 2019), or by aerosol (Mishra and Wimmer, 2017). even microorganisms, to transform lignin (modified or unmodified
However, many authors use this term to describe the process of forming powders) into nanoparticles is also gaining strength and needs to be
nanoparticles. further stimulated and studied.
A brief comparison among the main methods of synthesis LNPs
4.8. Comparison between methods addressing its main advantages and disadvantages are shown in Table 2.
The methods used in synthesising LNPs can be compared in terms of 5. LNPs application
solvent consumption, environmentally-safe, process time and cost,
nanoparticle stability and yields. The solvents used (THF, DMSO, The chemical composition of LNPs, as well as the size, shape, surface
acetone, dioxane and many others) are produced at the laboratory level, charge, hydrophobicity and the presence or absence of functional groups
have a relatively affordable cost, and are used in medium volumes (Beisl or other chemicals, are important characteristics that will define their
et al., 2017). The solvent shifting method has the highest solvent de potential application (Table 1). For example, in medical application, the
mand. According to the latest published studies, a concentration greater desired size of nanoparticles administered orally or intravenously
than 40 mg/mL of dry lignin in a solvent can make it difficult to dissolve should be between from 10 to 200 nm. The size below 200 nm allows for
when it reaches its saturation point. Thus, considering a yield of around
50% in this method of LNP synthesis, for each gram of lignin, 0.5 g of
LNPs are recovered, which requires 100 mL of solvent. The use of sol Table 2
vents, therefore, makes the process costly. Making a comparison be Overview of the advantages and disadvantages of the main methods used in
LNPs synthesis.
tween solvents for lignin, the price of 1 L of acetone (Sigma-Aldrich®), is
around USD 16.00 while THF (Sigma-Aldrich®) can reach USD 40.00. Method Advantages Disadvantages
Therefore, the choice of solvent is decisive in the pricing of LNPs. Anti-solvent - Good lignin dissolution - High cost of some solvents
However, the advantage is that they can be recovered and reused in a precipitation - Synthesis of LNPs with - Difficulty in solvent
new LNPs synthesis. Taking into account acetone, which has a low desired sizes and recovery
morphologies - Toxicity of some solvents
boiling point, it is possible to reach 95% recovery of the solvent by
- Use of low cost anti-
vacuum rotatory evaporator, which is already more difficult for other solvents (e.g. water)
solvents that have a high boiling point, such as DMSO (189 ◦ C). Other
methods, such as crosslinking and polymerization, although they are - High yield LNPS
simple, are based on hazardous reagents, like epichlorohydrin, hydrogen Solvent exchange/ - Good lignin dissolution - High price of some
Solvent shifting - Synthesis of LNPs with solvents
peroxide and others (Beisl et al., 2017). Nanoprecipitation by pH shift desired sizes and - Difficulty in solvent
ing also use unfriendly reagents and the few studies published at this morphologies recovery
moment, report low LNP yields. - Use of low cost anti- - Toxicity of some solventes
Progress in the development of greener methods for the synthesis of solvents (e.g. water) - High cost of dialysis
- High yield LNPS membranes
LNPs is ongoing, replacing toxic and harmful chemicals and equipments.
Ultrasonication - Fast LNPs synthesis - LNPs with irregular shape
An example is the use of “green” solvents, such as levulinic acid, - Green synthesis of LNPs and morphology
considered a novel sustainable solvent for lignin dissolution (Melro - Low cost of LNPs - Low yield of LNPs
et al., 2020). Among the fewer green and facile methods available until synthesis
now for producing LNPs, it is possible to highlight a simple and effective Interfacial - Good lignin dissolution - High cost and toxicity of
crosslinking/ - Synthesis of LNPs with some crosslinking agents
approach to fabricate LNPs with tuneable sizes based on using different Polymerization desired sizes and
lignin fractions (with different molecular weight and contents of hy morphologies
drophilic groups) by antisolvent precipitation (ethanol/water + dial Aerosol flow - Single step process - High cost and toxicity of
ysis), resulting in small-size LNPs (21 nm) with promising applications - High yields some solvents
- Absence of liquid
in fields like drug delivery, water treatment, nanofillers or antioxidants
byproducts (liquid anti-
(Ma et al., 2020). Other methods, like the one pot synthesis of LNPs with solvent)
compressed liquid carbon dioxide as an antisolvent (Myint et al., 2016); Biological pathway - Simple and low cost - LNPs with irregular shape
LNPs self-assembly in a recyclable and non-toxic aqueous sodium p- synthesis and morphology (usually
toluenesulfonate solution (Chen et al., 2019), Ag-LNPs production with - Green synthesis of LNPs macro size)
- Low yield of LNPs
cost-effectiveness and less toxic behaviour by heating at 80 ◦ C for 30 min
13
systematic administration in the circulatory system and into targeted 5.1. Antioxidant activity
tissue, evading the biological particles filters in the human body (Kim
et al., 2013; Tran and Webster, 2010). Beyond application in the Lignin, in its native state, is characterized by a complex chemical
biomedical field, LNPs with dimensions below 100 nm are an interesting structure that contains aromatic rings of the methoxy and the hydroxyl
new smart nano-sized coating beginning to be used on an industrial scale groups, is known to have antioxidant characteristics (Kai et al., 2016a).
and in information technology (Myint et al., 2016; Cazacu et al., 2013). However, studies involving LNPs have shown that when lignin is
LNPs with size above 200 nm can be applied to different cosmetic transformed into a nanoparticle, its antioxidant activity is increased
products. For instance, LNPs can be topically applied on the skin and as (García et al., 2010; Dong et al., 2011). This can be explained by the
UV-protectant sunscreens, although studies have shown that it is diffi greater amount of phenolic groups on the surface of the nanoparticle
cult for nanoparticles over 10 nm in diameter to penetrate through the that will be reacting with radical DPPH, consequently reducing it (Tre
stratum corneum into viable human skin by passive diffusion (Prow visan and Rezende, 2020). Furthermore, with the carboxyl and hydroxyl
et al., 2011; Watkinson et al., 2013). In addition, regulatory approval is groups on the surface of LNPs, they have the advantage of being solu
an important step towards releasing the use of LNPs in the areas of bilized in water. This increase in antioxidant activity of LNPs can be
health (biomedical and cosmetics) and food, which requires testing the directly applied to pharmaceuticals, cosmetics and food processing.
safety and effectiveness of LNPs. The main and most recent application Yearla and Padmasree (2016) evaluated the antioxidant potential of
of LNPs will be discussed as follows. hardwood dioxane lignin (DL), softwood alkali lignin (AL) and their
respective nanoparticles (DLNP and ALNP) by monitoring the decrease
Fig. 6. Antioxidant activities for LNP in the methanol/DPPH solution: (a) Absorbance (at 517 nm) and colour variation of the DPPH methanol solution for (from left
to right) control, pristine, HCl 2.5, H2SO4 2.9 and H3PO4 2.6 lignin solutions. (b) Inhibition halos measured at 5% and 8% of LNPs (HCl precipitated, pH 2.5) against
Pseudomonas syringae, Xanthomonas arboricola and Xanthomonas axonopodis. Reprinted with permission from (Yang et al., 2018a), Copyright (2018) American
Chemical Society.
14
in absorbance of DPPH radical. All compounds have superior antioxi (Fig. 7). They found that the blended creams with LNPs have lower
dant activity when compared with standard food antioxidants, such as transmittance in the visible region in comparison to commercial sun
butylated hydroxytoluene (BHT) and ascorbic acid (Asc). However, the screens with SPF 30. However, sunscreen lotions prepared with LNPs
radical scavenging ability of DLNP and ALNP was higher compared to look similar to tinted creams. Moreover, as the LNP concentration in
their parent polymers. Yang et al. (2016a) investigated the antioxidant creases, the greater the UV protection. The undesirable dark colour of
potential of lignin nanoparticles in polyvinyl alcohol (PVA)/chitosan lignin would be an important aspect for its utilization in certain appli
(CH) films for active packaging using DPPH radical scavenging activity. cations, such as cosmetic products (Dong et al., 2011); thus, reaction-
Interestingly, the incorporation of LNPs in PVA and CH films increased free lignin whitening is an important, that can be achieved through
the scavenging activity notably, highlighting the antioxidation response. acetylation of lignin and subsequent transformation into nanoparticles
Yang et al. (2018a) also investigated the potential of LNPs fabricated (Qian et al., 2014c). In addition, cyto and ecotoxicity tests of LNPs in
from pristine lignin (from Arundo donax). Tested by DPPH, the authors sunscreens need to be performed to ensure the safety of LNPs. Still, in the
found that both pristine lignin and isolated LNP by acids have strong impossibility of developing 100% biodegradable sunscreens, hybrid
antiradical activity, with a 40% increase in antioxidant activity for LNPs emulsions of LNPs with metallic nanoparticles currently used in sun
in comparison with the native lignin (Fig. 6a). screens, that ensure recommended SPF, could be a first step to launch
the product to the market.
5.2. UV-protectant and sunscreen elaboration
5.3. Antimicrobial activity
The antioxidant ability of lignin can be applied to protect against
ultraviolet radiation. It is known that UV radiation causes intracellular LNPs have also antimicrobial properties. Richter et al. (2015) have
oxidative damage in Escherichia coli, causing their mortality. Taking this successfully developed lignin nanoparticles infused with silver ions and
into account, Yearla and Padmasree (2016) verified that LNPs produced coated with a cationic polyelectrolyte layer for antimicrobial purposes
from seabul stems demonstrated high protective UV activity compared (Fig. 8). The nanoparticles synthesized have demonstrated excellent
to native lignin, suggesting that these LNPs can be incorporated into effectiveness in killing bacteria, such as Escherichia coli, Pseudomonas
industrial formulations. Gutiérrez-Hernandez et al. (2016) studied the aerugionosa and Ralstonia sp., since these LNPs adhere to the cell wall,
photoprotection characteristics of LNPs produced from Agave tequilana negatively charging it. Marulasiddeshwara et al. (2017) evaluated the
in association with ZnO nanoparticles. The LNPs were able to absorb antibacterial and antifungal activity of lignin capped silver nano
both UV-B and UV-C regions, which improves the solar protection factor particles. These particles showed antibacterial and antifungal activity
(SPF) value of sunscreens compared to without LNPs assays. Later, Wang against human pathogens Staphylococcus aureus, E. coli and Aspergillus
et al. (2019) examined the UV absorbing ability of LNPs. They found that niger and the zone of inhibition percentage was found to be 10%, 12%
it was possible to increase the SPF value by 115% when LNPS are added and 80%, respectively. Yang et al. (2018a) evaluated the antimicrobial
to pure cream (at a concentration of 5% nanoparticles). The use of LNPs activity of LNPs towards plant pathogens. Pseudomonas syringae pv to
in sunscreen cream is explained by the functional methoxyl groups and mato resulted in the most susceptible at both concentrations of 5% and
S- and G-type lignin easily absorbing UV in a significant manner. The 8% wt, being observed greater inhibition halos with higher concentra
aromatic compounds present in lignin and their interactions (π-π tion of nanoparticles. When LNPs were tested at 8% wt, Xanthomonas
stacking) are the key to the good effect of sunscreen mixed with LNPs arboricola resulted more susceptible than Xanthomonas axonopodis by
(Wang et al., 2019), being LNPs considered an excellent emulsion sta measuring inhibition halos of 0.36 mm and 0.33 mm, respectively
bilizer. Trevisan and Rezende (2020) also investigated the ability of (Fig. 6b). Aadil et al. (Aadil et al., 2019) also produced silver nano
LNPs produced from elephant grass to absorb UVA and UVB light particles using acacia lignin and tested them against gram-positive
Fig. 7. Comparison of UV–vis transmittance between neutral creams blended with different LNPs concentrations, acetylated LNP (AcLNP) and commercial sun
screens with fps 30. Reproduced from (Trevisan and Rezende, 2020) with permission from Elsevier, copyright 2020.
15
Fig. 8. Schemes of comparison between bactericidal action of environmentally benign lignin core nanoparticles (EbNPs) and common silver nanoparticles (AgNPs).
(a) Antimicrobial action of AgNPs via Ag+ ions delivery, which remains active after release (b) Antimicrobial action of Ag+ ion-infused EbNPs with a cationic
polyelectrolyte coating that promotes electrostatic adhesion to the bacterium’s cell wall, making it negative. (c) TEM micrograph of EbNPs (d) Confocal microscopy
image of EbNPs adhering to the cell membrane of E. coli. Reproduced from (Richter et al., 2015) with permission from Springer Nature, copyright 2015.
bacteria (Bacillus subtilis, Bacillus circulans and S. aureus) and gram- Varma, 2020). Dai et al. (2017) developed LNPs assembled with the
negative bacteria (E. coli, Ralstonia eutropha and P. aeruginosa) in polyphenolic antioxidant molecule resveratrol (RSV) and Fe3O4 mag
nutrient agar medium plates. It was observed that the lignin‑silver netic nanoparticles leading to the formation of a nanodrug carrier
nanoparticles were effective against a wide variety of bacteria, the (Fig. 9). The magnetic RSV-loaded lignin nanoparticles showed a good
higher the concentration, the higher the inhibition, including showing anticancer performance, tumor reduction, controlled in vitro RSV
better results than the control erythromycin, suggesting resistance of release and stability, mitigating adverse effects of using the drug alone.
some bacteria against the antibiotic. In addition, LNPs demonstrated In addition, there were no harmful effects on cells and mice. Tortora
very low in-vitro cytotoxicit against MCF-7 cell lines (Breast cancer et al. (2014) developed oil-filled lignin microcapsules and evaluated
cells), according to MTT assay. Recently, Xiao et al. (2019) developed their storage and delivery of hydrophobic molecules. In this work, lignin
hybrid lignin‑silver nanoparticles that showed excellent bactericide microcapsules incorporated and release Coumarin-6 in Chinese hamster
rates for E. coli and S. aureus, eliminating almost 100% of the bacteria. ovary cells successfully, being not-toxic for use in living beings. Pour
moazzen et al. (2020) developed cholesterol modified lignin nano
5.4. Delivery system particles, highly hydrophobic, used for drug delivery (folic acid) with a
pH-responsive release in vitro. The maximum release profile was around
One of the most promising applications for nanoparticles derived 55%, at pH 8.0 Zikeli et al. (2020) prepared a lignin nanoparticle with
from lignin is their use in the release of different compounds. Figueiredo entrapped essential oil for biocide delivery system. It was verified that
et al. (2017a) developed pure LNPs and infused-LNPs with iron (Fe3) and the entrapped oils (common thyme and wild thyme essential oil) were
iron oxide (Fe3O4) with low cytotoxicity against different cell lines and gradually released, in a slower way, in comparison to the non-trapping
low hemolytic rates (10–12%) after an incubation time of 12 h. These state, giving insights developing new systems for wood preservation.
LNPs were used for drug delivery against cancer cell proliferation. These Lignin-based nanoparticles can also be used for gene delivery into
nanoparticles were used as carriers for drugs that are poorly soluble in human cells, as proposed by Ten et al. (2014). The authors synthesized
water, such as sorafenib and benzazulene, enhancing their anti lignin nanotubes (LNTs) and used them to deliver DNA into human
proliferation effect in different cancer cells. Indeed, different functional cervical adenocarcinoma cells (HeLa cells) without needing auxiliary
groups present in lignin, such as OH and COOH, can be modified for agents since LNTs were much less toxic than carbon nanotubes (CNTs),
targeted tumor therapy and may be used for drug delivery (Iravani and highlighting the potential of LNTs for gene therapy, including in
16
Fig. 9. Self-assembled of lignin with resveratrol (RSV) and Fe3O4 magnetic nanoparticles (scheme above). Different concentrations of RSV formulations in tissue
distribution and tumor reduction after 24 h (a) and 48 h (b). RSV concentration in tumor issues post i.v. injection (c). Body weight (d), tumor inhibition (e), and
survival rates (f) of tumor-bearing mice with different formulations. Tumor photographs from different groups on day 20 (g). Reprinted with permission from (Dai
et al., 2017), Copyright (2017) American Chemical Society.
comparison with viral vectors, which tends to be more immunogenic. 5.5. Encapsulation
Liu et al. (2015) synthesized poly(2-dimethylaminoethyl methacrylate)
(LnPDMAEMA)-lignin copolymers by ATRP and evaluated in vitro gene Polymers have the ability to self-organize and this property can be
transfection for the LnPDMAEMA copolymers in different cell lines. It used for the production of micelles or capsules with several applications
was found that the smaller the chain size of the copolymer, the lower the (Duval and Lawoko, 2014). Yiamsawas et al. (2014) produced lignin
cytotoxicity. The assays also demonstrated that the gene transfection nanocapsules by interfacial polyaddition in inverse mini-emulsions. The
was performed successfully. As a viable application, delivery systems lignin solubilized in water was emulsified in an organic phase of
stand in the way of the safety of using LNPs as nanocarriers of substances cyclohexane containing a biosurfactant, originating hollow nano
in target living organisms. However, the latest published studies capsules. These lignin nanocontainers can be loaded with hydrophilic
demonstrate that the LNPs employed exhibited low cytotoxicity at substances that can be released by an enzymatic treatment, such as those
concentrations up to 100 mg/mL in different cell lines and low in vitro mediated by laccases. The encapsulations of hydrophobic compounds
hemolysis (Figueiredo et al., 2017a); are not cytotoxic and readily can be used for agricultural applications. Bertolo et al. (2019) also used
incorporated in the chinese hamster ovary cells (Tortora et al., 2014) LNPs for Pickering emulsions for bioactive compound encapsulation,
and do not cause changes in the ratio of mice white blood cells and such as curumin. Chen et al. (2016) synthesized lignin nanocapsules for
platelets nor cause risk of hypersensitivity (Dai et al., 2017). As a key the controlled release of the hydrophobic molecule coumarin-6. As re
factor, the safety verified in the LNPs in the studies already carried out ported, the release of encapsulated coumarin-6 was better in pH below
strengthens the future studies of biocompatibility of the LNPs in human 5.0.
bodies.
17
5.6. Hybrid nanocomposites nanomaterials.
One of the most interesting applications in LNPs is its use in com 5.7. Tissue engineering
bination with other nanocomposites, forming hybrid nanocomposites.
Thus, LNPs can also been used as a strengthening agent in polymer Recently, as mentioned before, studies demonstrated that lignin can
matrix and nanocomposites, providing better characteristics to bio be converted into nanofibers, hydrogels and others nanocomposites for
materials when in the absence of lignin [Chauhan, 2020). These hybrid tissue engineering, a promising tool used for repairing, replacing and
compounds made with LNPs have different applications. For example, enhancing the function of a specific tissue or organ (Figueiredo et al.,
Gupta et al. (2015) made use of LNPs as reinforcing agents to biopoly 2018; Furth et al., 2007). The development of structures suitable for cell
(trimethylene terephthalate) (bio-PPT) hybrid nanocomposites that had growth in vitro and in vivo is the biggest bottleneck to be overcome in
1.5% weight LNPs, improving some mechanical features of nano this technology, making its use in body tissue viable (Kai et al., 2016b).
composites, compared to bio-PTT, mainly tensile flexural and impact Diao et al. (2014) proposed a model of copolymer consisting of lignin
properties. Chen et al. (2019) also added LNPs to a polyacrylamide and grafted poly(N-isopropylacrylamide), poly(ethylene glycol), and
hydrogel (polyacrylamide/LNP), improving considerably the compres poly(propylene glycol), using ATRP technique. The copolymers dis
sive, tensile strengths and recoverability of the hybrid nanocomposite. played thermogelling behaviors which makes the use of these hydrogels
He et al. (2019) also developed poly (vinyl alcohol) (PVA) nano advantageous, since they are injectable and take shape inside the tissue,
composite films containing unmodified and modified lignin nano which avoids the need for surgery. Kai et al. (2015a) fabricated
particles (LNP and MLNP), respectively. The analyses revealed that biocompatible electrospun nanofibers through copolymerization of
MNLP nanocomposite have higher dimensional stability and reduce the lignin onto poly(methyl methacrylate) (PMMA) by ATRP and blending
moisture wicking, besides presenting good antioxidant activity and UV with poly(e-caprolactone). These hybrids nanocomposites showed a
absorption. Gan et al. (2019) developed a plant-inspired adhesive good performance in human dermal fibroblasts proliferation, attach
hydrogel based on Ag-lignin nanoparticle. The eco-friendly hydrogel ment and interactions. Certainly, the interaction tests with living tis
was gelled from an aqueous precursor solution containing Ag-lignin NPs, sues/organs and the cytotoxicity of these nanomaterials will be the
pectin, and acrylic acid (AA) at room temperature. Among the advan biggest challenge for approval by regulatory bodies.
tageous characteristics of this hybrid nanocomposite is a repeatable and
long-term adhesion, credited to dynamic redox catechol chemistry,
promoting it appropriated for surgical operation or other biomedical 5.8. Adsorption of heavy metal
applications. Yang et al. (2019a, 2019b) found that it is advantageous to
incorporate LNPs in a phenol–formaldehyde resol resin, since LNPs Recently, studies have focused on the development of new applica
disperse better than micro lignin (LMP). In this unprecedented work, it tions for LNPs. Zhang et al. (2019), for example, innovated by synthe
was checked that, due to the aromatic-phenolic characteristics of lignin, sising hybrid nanoparticles using epichlorohydrin as a cross-linker
both LNPs and LMP favor the thermal cure process, with LNPs being between amino-functionalized magnetic nanoparticles and lignin. These
more reactive with the resin. Recently, Qi et al. (2020) evaluated the lignin-based hybrid magnetic nanoparticles exhibited high absorption
potential of a nanocomposite of LNPs based polyurethane and found that capacities of Pb+2 and Cu+2. Xiao et al. (2019) synthesized a lignin-
the hybrid compound showed inherent resistance towards UV radiation, based nano-trap (LBNT) capable of adsorbing different heavy metal
frequency dependent behaviour for electrical conductivity and good ions. It was possible to reduce from 5 ppm to a range of 3–9 ppb six
thermal reprocessability. The same group, prepared different films of different heavy metals (Ag (I), Hg(II), Cd(II)) and borderline (Pb(II), Cu
lignin microparticles (LMP) onto Poly (lactic acid) (PLA) and mixed by (II), Zn(II)), using LBNT. It exhibited high adsorption capacity of silver
fusion with ethylene-vinyl acetate-glycidyl methacrylate (NPG). These ions in water. Dai et al. (2019) also reported one ingenious technique for
PLA/NPG/LMP films demonstrated excellent resistance to UV and green mussel-inspired lignin magnetic nanoparticles that showed a high
antioxidant activity (Yang et al., 2020a). Furthermore, biodegradable adsorptive capacity of chromium (III) and its removal in wastewaters.
hybrid composite based on poly (lactide-ε-caprolactone) grafted with
LNPs were also developed. The biomaterial demonstrated an increase in 5.9. Other applications
toughness with the incorporation of LNPs, in addition to being able to
protect almost 100% of UV-B and UV-C irradiation, and can be used in • Flocculation.Yin et al. (2018) took advantage of the properties of
sunshade and food packaging areas (Yang et al., 2020b). Yang et al. lignin nanoparticles and assembled them with gelatine to constitute
(2020c) also investigated the capacity of a bio-based Polyvinyl alcohol an LNP-gelatine complex as a novel flocculant for S. aureus and
(PVA) nanocomposite film prepared with LNPs, nanocrystalline cellu E. coli. The LNPs-gelatine complexes achieved a flocculation effi
lose (CNC) cross-linked by means of glutaraldehyde. The presence of ciency higher than 95% within 30 min at pH 4.5 and can be designed
LNPs increased the anti-oxidant activity of the film, as well as protection to be used in wastewater treatment, as a nano-trap.
against IV reactions, improved thermal stability and tensile strength. • Immobilization of enzymes. Lignin nanoparticles can also be used
Finally, the authors found that the nanocomposite film functioned as a directly in biorefineries, the place where the raw material for its
good water vapour barrier. In order to further improve the properties of production comes from. Dong et al. (2019) were one of the first to
these hybrid nanocomposites, it is common to subject them to physical/ think about it. They developed lignin magnetic nanoparticles
chemical/biological modifications. He et al. (2018) employed citric acid (Fe3O4/LSQA) to immobilize and recover cellulase, controlled by pH
as an eco-friendly modifier of both cellulose nanocrystals (CNC) and variation (Fig. 10). The idea worked well, and a high immobilization
lignin nanoparticles (LNP). Modifications of etherification (in CNC) and ratio of cellulase (55.52%) was achieved with a lower desorption
esterification (in LNP) resulted in a better dispersion of these nano ratio (68.27%), even after adjusting the pH of the system. Still, after
materials in polar solvents and an increase in thermal stability. LNPs five reusing cycles, the desorbed cellulase retained about one third of
being part of hybrid nanocomposite have also been developed for other its relative activity.
applications in agriculture, forestry, soil rehabilitation, controlled • Dye removal.Azimvand et al. (2018a) prepared lignin nanoparticles
release of fertilizers (Figueiredo et al., 2018), adsorption of heavy metal and lignin nanoparticle-g-polyacrylic acid adsorbent to remove
(Zhang et al., 2019), flocculation (Yin et al., 2018), tissue engineering Safranin-O from an aqueous solution. The lignin nanoparticle-g-
(Diao et al., 2014) and others. The challenges encountered in the use of polyacrylic acid adsorbent demonstrated greater adsorption capac
LNPs in hybrid nanocomposites are to assess their safety and effective ity (138.88 mg/g) in comparison to lignin nanoparticle (99 mg/g) of
ness by regulatory bodies, as well as the biodegradability tests of these dye, highlighting the potential of these nanoparticles to be employed
18
Fig. 10. (a) Lignin-based magnetic nanoparticles (Fe3O4/LSQA) used in immobilization and recovery of cellulase. (b) Immobilization time, where mass ratio was 1:1,
and the immobilization temperature was 40 ◦ C, pH 4.8. (c) Desorption ratio of immobilization cellulase at different pH. Reproduced from (Dong et al., 2019) with
permission from Elsevier, copyright 2019.
in bioremediation. Azimvand et al. (2018b) also used LNPs to the in vitro controlled release of these essential oils, which ends up
remove Basic Red 2 dye from aqueous solution (81.9 mg/g). making it a more effective biocide, since these oils are very volatile;
• Food packaging. Taking advantage of the antioxidant and antibacte (b) as nanoadsorbent of target compounds that can be used as bio
rial capacity of LNPs, Yang et al. (2016a) used LNPs as filler in fertilizers, as recently performed by Li et al. (2020), that developed
polyvinyl alcohol/chitosan films and antimicrobial assays revealed magnetic lignin-based nanoparticles to adsorb phosphorus from
the capacity to inhibit the bacterial growth of Erwinia carotovora wastewater and then used them as renewable slow release compound
subsp. carotovora and Xanthomonas arboricola pv. pruni over time. fertilizers in agriculture.
The applicability of LNPs in nanocomposites could be extended to
increase the safety and shelf life of packaged foods, since they would 6. LNPs challenges and perspectives
act against bacterial plant/fruit pathogens. The same group pro
duced LNPs and cellulose nanocrystals, that when combined with The fact that lignin is a heterogeneous molecule, with aromatic and
neat or grafted poly (lactic acid), showed antibacterial activity with phenolic units that establish different bonds, reinforces the idea of lignin
reduced multiplication of the bacterial plant pathogen Pseudomonas valorisation into nanoparticles is a sustainable technological solution,
syringae that attack tomato crops. These features can be applied in with enormous potential for applicability today. The first and greatest
the food packaging sector (Yang et al., 2016b). challenge of this technology is still in efforts to understand in more detail
• Wound dressing. Nanofiber wound dressings have received a lot of the process of formation of LNPs, in particular, the controlled formation
attention recently, mainly due to their excellent skin biocompati of spherical nanoparticles, with the desired size, which adds value to
bility properties and protection against environmental effects (Reesi their applications, mainly in the biomedical field. Other obstacles in
et al., 2018) The potential for using LNPs can also be extended to LNPs panorama lie in faster, simpler and more eco-friendly methods of
their use in hybrid compounds for wound dressing. Reesi et al. production as well as new and/or combined applications, following the
(2018) developed a gel that contains lignin nanofibers (LigNFs) concept “waste” to “wealth”. Although LNPs offer many opportunities
modified by arginine molecules (Arg-Lig-NF gel). The in vivo ana for high-value applications, they can still be much more explored (Zhao
lyses, conducted on rats, allowed to conclude that the wound dres et al., 2016). In comparison with metallic and organic materials that are
sing developed Arg-Lig-NF gel can accelerate the cicatrisation, used in chemical industry and biotechnology, biopolymers have
besides increase re-epithelialization, collagen deposition, and stim received attention due their environmentally-friendly benefits,
ulate the formation of new blood vessels. Next step consists of deeper nonhazardous (Vinardell and Mitjans, 2017), biocompatibility (Fig
clinical tests for future approval in humans, without side effects. ueiredo et al., 2017a; Figueiredo et al., 2017b) and low cost of prepa
• Agriculture. Lignin nanoparticles also have a wide potential for ration (Iravani and Varma, 2019; Iravani and Varma, 2020).
applicability in agriculture, which can be used: (a) to entrapped Given the current knowledge about lignin nanoparticles and
desired compounds and controlled release as proposed by Zikeli et al. considering the existing gaps in the development of this technology, we
(2020), that entrapped essential oils in LNPs and positively evaluated can list future actions to overcome the main feasibility hurdles and the
19
commercialization of LNPs becomes a reality: Assis, C.A., Greca, L.G., Ago, M., Balakshin, M.Y., Jameel, H., Gonzalez, R., Rojas, O.J.,
2018. Techno-economic assessment, scalability, and applications of aerosol lignin
micro- and nanoparticles. ACS Sustain. Chem. Eng. 6, 11853–11868.
- Lignin price. It is necessary that studies focus on using low cost lignin Azimvand, J., Didehban, K., Mirshokraie, S.A., 2018a. Safranin-O removal from aqueous
as a raw material and, preferably, in higher concentrations. solutions using lignin nanoparticle-g-polyacrylic acid adsorbent: synthesis,
- Greener methods for the synthesis of LNPs. Use of more economical, properties, and application. Adsorpt. Sci. Technol. 36 (7–8), 1422–1440.
Azimvand, J., Didehban, Kh., Mirshokraie, S.A., 2018b. Preparation and characterization
green, and easily recoverable solvents is a key point to achieve the of lignin polymeric nanoparticle using the green solvent ethylene glycol:acid
sustainable requirements, as well as its safety and effectiveness. precipitation technology. BioResources 13 (2), 2887–2897.
- Scale-up process. Investments in large-scale, fast, low cost LNP pro Becker, J., Wittmann, C., 2019. A field of dreams: lignin valorization into chemicals,
materials, fuels, and health-care products. Biotechnol. Adv. 37, 107360.
duction processes that consume less energy need to be made to bring Beckham, G.T., Johnson, C.W., Karp, E.M., Salvachúa, D., Vardon, D.R., 2016.
LNPs industrialization and fast-track commercialization. Life cycle Opportunities and challenges in biological lignin valorization. Curr. Opin.
assessment of a lignin nanoparticle biorefinery is crucial. Biotechnol. 42, 40–53.
Behin, J., Sadeghi, N., 2016. Utilization of waste lignin to prepare controlled-slow release
- Regulatory hurdles. Tests of safety and effectiveness of LNPs in urea. Int. J. Recycl. Org. Waste Agricult. 5, 289–299.
computational modulations (in silico) and clinical trials (in vitro and Beisl, S., Miltner, A., Friedl, A., 2017. Lignin from micro- to nanosize: production
in vivo), as well as the interaction of LNPs in target cells/tissues need methods. Int. J. Mol. Sci. 18, 1244.
Bertolo, M.R.V., de Paiva, L.B.B., Nascimento, V.M., Gandin, C.A., Neto, M.O.,
to be carried out for approval and advances in the next stages of use. Driemeier, C.E., Rabelo, S.C., 2019. Lignins from sugarcane bagasse: renewable
- New LNPs applications. Discover new application of LNPs to strategic source of nanoparticles as Pickering emulsions stabilizers for bioactive compounds
areas that can replace synthetic nanoparticles or even those coming encapsulation. Ind. Crop. Prod. 140, 111591.
Camargos, C.H.M., Silva, R.A.P., Csordas, Y., Silva, L.L., 2019. Experimentally designed
from natural materials, but which are high carbon consumers, would
corn biomass fraction to obtain lignin nanoparticles and fermentable sugars. Ind.
be a gain for the viability and commercialization of LNPs. Crop. Prod. 140, 111649.
Carvalho, W., Canilha, L., Ferraz, A., Milagres, A.M.F., 2009. Uma visão sobre a
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Acknowledgements carrier for the efficient delivery of resveratrol. ACS Sustain. Chem. Eng. 5,
8241–8249.
This work was supported by University of Caxias do Sul (UCS) and Dai, L., Li, Y., Liu, R., Si, C., Ni, Y., 2019. Green mussel-inspired lignin magnetic
nanoparticles with high adsorptive capacity and environmental friendliness for
the National Council for Scientific and Technological Development chromium (III) removal. Int. J. Biol. Macromol. 132, 478–486.
(CNPq) (Processes 314897/2018-6, 407228/2018-7 and 159875/2018- Del Saz-Orozco, B., Oliet, M., Alonso, M., Rojo, E., Rodriguez, F., 2012. Formulation
8). We are also grateful to Mr. Gionathan Sandi, for his consultancy on optimization of unreinforced and lignin nanoparticle-reinforced phenolic foams
using an analysis of variance approach. Compos. Sci. Technol. 72, 667–674.
the graphic design of the figures.
Deng, Y.H., Feng, X.J., Zhou, M.S., Qian, Y., Yu, H.F., Qiu, X.Q., 2011. Investigation of
aggregation and assembly of alkali lignin using iodine as a probe.
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Lignin Nanoparticles Enter The Scene A Promising Versatile Green Tool For Multiple Applications

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Biotechnology Advances 47 (2021) 107685

Contents lists available at ScienceDirect

Research review paper

1. Introduction basic unit is called p-hydroxyphenyl (non-methoxylated, derived from

Biotechnology Advances 47 (2021) 107685

Solvent Exchange/Solvent shifting

Biotechnology Advances 47 (2021) 107685

muscles, Strong underwater antifouling

Biotechnology Advances 47 (2021) 107685

Biotechnology Advances 47 (2021) 107685

Interfacial crosslinking consists of a process of lignin emulsification, 4.7. Other methods

5.6. Hybrid nanocomposites nanomaterials.

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