Levy et al.

Journal of Biological Engineering (2019) 13:48

https://doi.org/10.1186/s13036-019-0173-4

REVIEW Open Access

Quantum dot therapeutics: a new class of

radical therapies
Max Levy1,2, Partha P. Chowdhury1,2 and Prashant Nagpal1,2,3*

Abstract
Traditional therapeutics and vaccines represent the bedrock of modern medicine, where isolated biochemical
molecules or designed proteins have led to success in treating and preventing diseases. However, several adaptive
pathogens, such as multidrug-resistant (MDR) superbugs, and rapidly evolving diseases, such as cancer, can evade
such molecules very effectively. This poses an important problem since the rapid emergence of multidrug-
resistance among microbes is one of the most pressing public health crises of our time—one that could claim
more than 10 million lives and 100 trillion dollars annually by 2050. Several non-traditional antibiotics are now
being developed that can survive in the face of adaptive drug resistance. One such versatile strategy is redox
perturbation using quantum dot (QD) therapeutics. While redox molecules are nominally used by cells for
intracellular signaling and other functions, specific generation of such species exogenously, using an
electromagnetic stimulus (light, sound, magnetic field), can specifically kill the cells most vulnerable to such species.
For example, recently QD therapeutics have shown tremendous promise by specifically generating superoxide
intracellularly (using light as a trigger) to selectively eliminate a wide range of MDR pathogens. While the efficacy of
such QD therapeutics was shown using in vitro studies, several apparent contradictions exist regarding QD safety
and potential for clinical applications. In this review, we outline the design rules for creating specific QD therapies
for redox perturbation; summarize the parameters for choosing appropriate materials, size, and capping ligands to
ensure their facile clearance; and highlight a potential path forward towards developing this new class of radical
QD therapeutics.
Keywords: Radical antimicrobials, Multidrug-resistant superbugs, Quantum dot therapeutic, Reactive oxygen species

Introduction hydroxyl radicals, and peroxynitrite ions [13, 15, 16].

Reduction and oxidation reactions form the core of most Therefore, careful choice of desired biological targets,
significant processes in biology, where the majority of bio- mechanistic insights into redox species and their outcome
logical interactions, signaling, and basic cellular biology inside a cell, and precise control over their intracellular
involves either a gain or loss of electrons or ionic species/ generation can provide a vital tool for precision or specific
radicals [1]. Most prominently, many redox species are killing of cellular species vulnerable to a chosen redox per-
regulatory and believed to be used for molecular signaling turbation, that can be triggered by stimuli to act as a
and as activators of stress response [2–6]. Others, how- therapeutic.
ever, can cause indiscriminate oxidative damage and dys-
function [7–12]. Chemical reactions such as Fenton
chemistry [13], enzymatic conversions, and disproportion- Designing for a “radical” approach
ation [14], can convert these species into others–such as While many traditional antibiotics have suffered failure
the conversion of superoxide into hydrogen peroxide, against adaptive resistance, a versatile approach to ad-
dress this dynamic problem is emerging. Where trad-
* Correspondence: [email protected] itional small-molecule antimicrobials struggled with
1
Chemical and Biological Engineering, University of Colorado Boulder, transport into gram-negative pathogen cell walls,
Boulder, CO 80303, USA nanoparticle-based therapeutics have shown remarkable
2
Renewable and Sustainable Energy Institute, University of Colorado Boulder,
Boulder, CO 80303, USA stability, ease of delivery, and facile transport through
Full list of author information is available at the end of the article cell walls due to their small size [17–21]. Once inside
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 2 of 12

the cell, the nanoparticle or QD therapy can make use of superoxide was found to be a potent bactericidal at low
the presence of oxygen, water, and if required, an exter- nanomolar doses—killing a range of multidrug-resistant
nal trigger. Therefore a wide range of reactive oxygen (MDR) pathogens without affecting the viability or growth
species (ROS, e.g. superoxide O2●-, hydroxyl OH●, sing- of host mammalian cells in in vitro measurements [19, 20,
let oxygen 1O2, and hydrogen peroxide H2O2) and react- 24, 29]. This difference in nanotherapeutic toxicity be-
ive nitrogen species (RNS, e.g. nitric oxide NO●, tween host and the targeted pathogen is important for de-
peroxynitrite ONOO−) can be formed intracellularly signing the safest possible treatment. Biological
using redox chemistry. Since these species are respon- specificity enables a treatment to effectively clear in-
sible for a broad range of physiology and pathology in fections while preserving the host cells. Although the
living organisms [22, 23], they have been investigated for superoxide anion has a high thermodynamic capacity
such potential applications as cancer therapies and novel to be a strong oxidant, its lack of reactivity with cel-
antimicrobials. Therefore, specific intracellular gener- lular components at physiological pH (largely due to
ation of these species can drastically affect the specificity electrostatic repulsion with negatively charged biomo-
of ROS/RNS therapy using the proposed redox lecules)--except for the inactivation of biosynthetic
perturbation. enzymes containing labile iron-sulfur clusters--is key
Recently, our group assessed these different ROS and to its selectivity [25, 30]. Further, the role of iron se-
RNS species as potential therapeutics [24]. Using these questration in host colonization makes pathogenic
species intracellularly, we determined their respective bacteria particularly vulnerable to superoxide com-
minimum inhibitory concentration (MIC) values. We pared to hosts [31, 32]. Therefore, while several ROS
found a bactericidal effect for several species at high species like hydroxyl radicals are indiscriminate oxi-
threshold concentrations (singlet oxygen: 1 mM; peroxide: dants and can readily oxidize proteins, lipids, and nu-
10 mM; hydroxyl radical > 10 mM; nitric oxide > 1 mM, cleic acids [8, 33], prior studies and our experiments
Fig. 1) [24, 25], where these redox species would be toxic indicate specificity in the of superoxide anions [19,
even for host mammalian cells [26–28]. However, 20, 24, 29, 34, 35]. Given the specificity of

Fig. 1 Identifying pathogen vulnerability using redox perturbation with different ROS. Compared to singlet oxygen and hydroxyl radicals,
superoxide and peroxide have much longer diffusion lengths and half-lives in the cellular environment (red circles, not to scale) [24, 82]. Singlet
oxygen and hydroxyl radicals are also more nonselective – they react rapidly with an abundance of endogenous biomolecules. Superoxide is
more selective, partly due to its negative charge, and it reacts with very particular consequential cellular targets such as iron-sulfur clusters [25].
The endogenous bacterial defense against superoxide is less abundant than the defense against nonselective ROS. This leads to a drastically
lower observed toxicity threshold when compared to other species [24]. Unlike other ROS, superoxide offers a large window of dosage that yields
toxicity in pathogens and nontoxicity in hosts [19, 24]
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 3 of 12

superoxide’s mechanism of action, the low MIC value nominal (bulk) bandgap values, we obtained a list of ‘fa-
for pathogens and higher tolerance in host mamma- vorable’ materials for the proposed QD nanotherapy.
lian cells, its long lifetime and large diffusion length Keeping in mind the extinction of light as it enters the
make it an ideal candidate for selective redox therapy. skin considering the most common constituents as
water, hemoglobin, melanin, etc. [20, 36, 37], there is a
Selective redox activation using quantum states window of nominal biological transparency (~ 800–1300
QDs, or semiconductor nanocrystals, have size-, shape-, nm wavelength), which narrows the material and band-
and composition-tunable quantum states for reduction gap considerations further (Fig. 2b-d). Materials which
and oxidation reactions. These states can be triggered by absorb violet and UV light are less suitable for QD
external electromagnetic radiation like light, and have nanotherapy—such short wavelengths of light will be
demonstrated a promising role in non-traditional redox quickly scattered or absorbed near the surface of animal
therapy [17–20, 24, 29]. Precise control over their tissue. This lack of penetration would make it extremely
photogenerated electron and hole states provides a challenging to use wide-bandgap materials to treat sys-
unique ability to tailor their photochemistry in the cellu- temic infections. Red and near-infrared absorbing QDs
lar environment, thereby providing control over intracel- would be far less susceptible to this issue. Therefore,
lular redox species. As the first step towards designing near-infrared materials like cadmium telluride (CdTe)
an effective QD therapeutic, we assessed a range of dif- [19, 20, 24, 29], copper indium sulfide (CIS2) [19], in-
ferent materials, along with their corresponding (bulk) dium phosphide (InP), and gallium arsenide (GaAs)
reduction and oxidation states (Fig. 2a). To select for could serve as good candidates for selective antimicro-
specific intracellular generation of superoxide, the reduc- bial, material stability, cytotoxicity, and surfaces [17, 18].
tion potential should exceed − 0.33 V on normal hydro- Using dopants and bandgap engineering, it is also pos-
gen electrode (NHE) scale. Simultaneously, to avoid the sible to improve the suitability of some other materials.
formation of other non-specific ROS species that can For instance, carbon QDs and silicon QDs have many
cause indiscriminate cell damage, the oxidation potential reported biological applications in bio-imaging, cancer
should be less than 1.8 V NHE. Using this metric as a se- therapy, as well as some reports describing ROS-medi-
lection criterion for selective redox antimicrobial ther- ated therapy [38–41]. Depending on particle size and
apy, and classifying the materials on the basis of their dopants,the optical properties of these materials can be

Fig. 2 Criteria for material selection for QD therapeutic against MDR superbugs. a) Conduction band (red) and valence band (blue) positions for
select semiconductors in bulk, according to references cited in reviews herein [83, 84]. Band edge positions shown in relation to thresholds for
superoxide (green) and hydroxyl radical (red) generation. Many of these materials only absorb ultraviolet light or are unable to generate superoxide. b)
By applying rational constraints to this list of materials, we can narrow this (non-exhaustive) list of candidates. c) These candidates could potentially
generate therapeutic superoxide using visible or NIR light, which penetrates deeper through tissue than UV (d), reproduced with permission from the
American Chemical Society37
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 4 of 12

specifically tailored to decrease the energy of light re- present issues of colloidal stability or inherent cytotoxicity.
quired for photoactivation [42]. The same approach can A good solution to enable using such materials could be
also be extended to metal oxide materials. to use that material as a redox-active core, covered by a
Due to several contradictory reports of ROS gener- thin shell of biocompatible material [29]. Further, material
ation and potential “therapeutic” action of two cytotoxicity is often tied to a nanoparticle’s physical size,
FDA-approved materials, zinc oxide (ZnO) and titanium hydrodynamic radius, and surface charge (zeta potential).
dioxide (TiO2) QDs and nanoparticles [43–49], we eval- These factors can directly affect a nanoparticle’s affinity
uated their redox properties and demonstrated bandgap for surrounding biomolecules and tissue. For example,
and redox state engineering approach proposed in this worsened zeta potential can hinder colloidal stability and
review. First, unmodified or undoped ZnO and TiO2 potentially result in particle aggregation. This could lead
nanoparticles were tested using electron paramagnetic to selective accumulation of QDs in some organs like kid-
resonance (EPR) spectroscopy technique. In order to ney, spleen, and liver [17, 18], where the host cells have
evaluate the short-lived radical species formed from small pore sizes, but are quickly cleared through the rest
redox chemistry, we used a spin-trapping method to of the organs and blood circulation. Nominally, QDs with
form more stable adducts. Both ZnO and TiO2 nanopar- a hydrodynamic diameter below ~ 10 nm can be cleared
ticles showed only hydroxyl radical formation upon exci- from the body in in vivo animal tests. After accumulating
tation with ultraviolet light above their bandgap in organs, due to lack of typical metabolism as seen in
(Fig. 3a,b). This would be problematic for potential small molecules, one hypothesis suggests the potential for
nanotherapy because both ultraviolet light and hydroxyl surface material leaching to occur, causing the QDs to
radicals are indiscriminately toxic to all cells. Careful “shrink” in size and clear away. This release of metal ele-
electrochemical measurements revealed that, while the ments could present unpredictable and undesired host
ZnO reduction potential is too low for superoxide for- toxicity issues. Therefore, the choice of biocompatible ma-
mation, its oxidation potential is very high—leading to terial, at least on the QD surface, can be critical for suc-
hydroxyl generation upon light activation (Fig. 3c,e). cessful application, reducing potential toxicity concerns
Therefore, even if ZnO nanoparticles were doped with a for host cells. Evidence in support of this hypothesis from
cation (to reduce the nominal reduction potential) or literature can be seen in Table 1 [85–104], where different
anion (to reduce the oxidation potential), the visible light core materials (like CdSe and CdTe) when coated with
absorbing nanoparticles still could not form superoxide other more benign/biocompatible materials, display a sig-
(Fig. 3e,g). This was further confirmed via electrochem- nificant reduction in toxicity. We reviewed a number of
ical measurements by removing oxygen, where direct such studies in literature with a wide range of sizes, hydro-
hole-injection into water leads to the formation of hy- dynamic radius, and in vitro and in vivo studies. As a re-
droxyl radical (Fig. 3c). Evaluation of TiO2 nanoparticles sult, we found that even large QDs with significant
showed more promising results, however. While the retention made of/coated with less toxic elements, dis-
oxidation potential of undoped TiO2 was too high, the played much lower cytotoxicity. Further, materials that do
reduction potential was suitably matched for superoxide not create any toxic ROS, such as hydroxyl or singlet oxy-
formation (Fig. 3d, f ). Therefore, anion-doped TiO2 gen, also displayed low cytotoxicity to the host cells. These
nanoparticles, in principle, should form therapeutic materials could be used either as stable single-material
superoxide. However, the presence of oxygen vacan- QDs, or as coating/shell for QDs with a different core ma-
cies and resulting Ti3+ ions nominally present on this terial better suited for redox perturbation.
oxide material surface [50–52] catalyzes rapid Fenton
chemistry to dismutate superoxide, converting it into QD ligands, size, and clearance
toxic hydroxyl radicals [53]. To prevent such un- Comparing data from identical QDs/nanoparticles with
wanted dismutation, we coated the surface of TiO2 different ligands, charge, and hence resulting different
nanoparticles with a zinc sulfide (ZnS) shell, and saw hydrodynamic radius, we observed significant differences
significant superoxide formation (in visible light) in their retention and cytotoxicity (Table 2) [18–20],
using anion-doped (N-doped) TiO2 core/ZnS shell [105–109]. Notably, even across materials with different
nanoparticles (Fig. 3f, h). toxicity, e.g. CdSe, CdTe, and Au, surface ligands clearly
influence retention and cytotoxicity. At identical QD/
Choosing the right material(s) for QD therapeutic nanoparticle core sizes, positively charged ligands (cyste-
While the choice of an appropriate redox-active material amine) show indiscriminate adhesion to different nega-
is important for selective therapeutic action, as shown tively charged biomolecules, creating a protein “corona”
above, the QD surface plays a key role in cellular photo- that increases its hydrodynamic radius significantly. This
chemistry and biocompatibility. Many materials have ap- effectively increases QD retention and resulting cytotox-
propriate redox properties to enable QD therapy, but icity [17, 18, 29, 54, 55]. Switching to negatively-charged
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 5 of 12

Fig. 3 Bandgap and redox state engineering for therapeutic radicals. a-b) EPR spectra for UV illuminated ZnO and TiO2 nanoparticles, respectively,
showing DMPO-OH peaks corresponding to the spin-trapped adduct of hydroxyl radicals. c-d) cyclic voltammograms for ZnO and TiO2, respectively, in
deoxygenated water. Without a source of oxygen, TiO2 generates no radical signal but ZnO shows a peak corresponding to hydroxyl
radicals – indicating superoxide-generating ability from TiO2 but not ZnO. e-f) reduction and oxidation state positions for ZnO and TiO2,
respectively, as well as the effects of doping. Anionic doping shifts the VB and cationic doping shifts the reduction potential. g-h) EPR
spectra for engineered ZnO and TiO2, respectively. Anionic and cationic doping of ZnO, as well as anionic doping of TiO2, yield hydroxyl
production with visible light. Cationic doping of TiO2 shows no radical signal – indicating reliance on the reduction potential for superoxide generation.
EPR spectra for N-TiO2/ZnS shows clear DMPO-OOH peaks corresponding to the superoxide radical adduct

ligands (mercaptopropionic acid) at same/similar core retention, with low/moderate toxicity. However, a simi-
size meanwhile reduces indiscriminate biomolecule at- larly sized zwitterionic-ligand (cysteamine) results in low
tachment and lowers/eliminates toxicity. This ligand still hydrodynamic radius and toxicity. These findings can be
results in higher hydrodynamic radius and higher explained by the lack of formation of a protein corona
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 6 of 12

Table 1 Review of in vitro and in vivo toxicity reported for relevant core/shell QDs [85–104]

and higher rates of renal clearance in in vivo animal (zwitterionic) to maintain a low-hydrodynamic radius,
studies. This points to a clear strategy of controlling the high rates of clearance, and low toxicity, can be
QD core/shell size, along with ligand and charge, so that employed for a suitable therapeutic bottom-up design
the total hydrodynamic diameter remains below 10–15 strategy for redox QD therapies.
nm. Taken together, this 3-layer design approach con-
sists of: 1) QD made with core material with tuned Future outlook/approaches
reduction-oxidation potentials for selective generation of Addressing host toxicity
superoxide for as antimicrobial for MDR superbugs; 2) There are three major potential sources of toxicity for
non-toxic and biocompatible shell core or shell material, the host mammalian cells that the current and future
resulting in high chemical stability and low material non-traditional QD therapeutics need to address: 1)
leaching and cytotoxicity; and 3) ligand design Acute material toxicity leading to loss of host cell
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 7 of 12

Table 2 Review of common charged ligands and reported effects on biodistribution and toxicity [18–20], [105–109]

viability or growth; 2) Oxidative stress; and 3) DNA cytotoxicity concerns in in vitro screenings, and only ad-
damage and carcinogenesis. To address these concerns, vance candidates that show clear differences in MIC
the QD therapeutics first need to address acute values for the host and pathogen cells. This can be
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 8 of 12

established by designing the mechanism of action after adjuvant nanoparticles (< 20–50 nm) which can evoke a
careful consideration of potential vulnerabilities in the stronger immune response, aiding the QD nanothera-
pathogen’s cellular environment and metabolism. This, peutic [56, 57], by acting as “Nano-Immunotherapy”
therefore, leads to a more directed and dynamic (Fig. 4a); and b) ~ 20–50 nm nanoparticles coated with
approach to counter the adaptive resistance in these [Fe-S] cluster [58] complexes as countermeasures, for
MDR pathogens. Similarly, the use of specific ROS like size-selective uptake in host cells (Fig. 4b), to reduce the
superoxide–which can be selectively toxic to superoxide concentrations and ROS stress in the host
iron-sequestering pathogens–creates a clear window for and protect them against any potential toxic mechanism
differences in MIC values between host and pathogens. (Fig. 4a).
This therapeutic window of concentration has been suc-
cessfully identified and utilized as a therapeutic in in Nano-Immunotherapeutics
vitro studies to target MDR pathogens, while preserving are a class of new immunomodulatory materials, where
host viability and growth. Further experiments are their physicochemical properties: size, shape, surface
needed to determine the transcriptomic response to charge, molecular weight, roughness, and hydrophobi-
superoxide therapy. More specifically, this is necessary city, are used to mimic normal cellular components and
to understand how oxidative stress from the proposed evade or suppress immune response (immune-evasive or
treatment affects the host. So far, the experimental evi- immune-suppressing), or designed to inflame the host
dence in literature points to non-perturbative stress re- immune response for potential therapeutic effect
sponse of the host to specific ROS like superoxide, and (immune-activating materials) [56, 57]. For instnace,
to a mechanism of action limited primarily to enzyme smaller nanoparticles have higher uptake and trafficking,
deactivation and indiscriminate DNA/RNA damage or allowing them to reach the lymph nodes—evoking
genotoxicity. higher levels of surface maturation markers and inflam-
To further alleviate these concerns, our lab is develop- matory cytokine secretion [59–61]. Further, asymmet-
ing two nanoparticle therapeutic adjuvant and “counter- rical shapes, such as nanorods, show similar trends in
measures”, made from FDA approved materials, to be their immune response: Nanorods with similar radius
supplied with the QD therapeutic: a) larger-sized but smaller length show higher uptake [61]. But longer

Fig. 4 Addressing QD toxicity and future directions. a) Schematic and summary of three proposed types of non-traditional therapeutic, adjuvant,
and countermeasure nanoparticles. QD therapeutics (top) using superoxide generation; Nano-immunotherapy (middle) using 20–50 nm benign
nanorods to trigger an immune response; and a countermeasure (bottom) using large or small benign nanoparticles coordinated with Fe-S to
serve as a host-specific nano-antioxidant. b) Depiction of host-specific protection using the larger nanoparticles coated with [Fe-S] clusters as
countermeasures against the superoxide ROS stress from QD therapeutic. c) Depiction of probiotic-specific protection using transcriptomic/
proteomic targeting with countermeasure nanoparticles
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 9 of 12

nanorods induced a higher inflammatory response hydrophobicity [63, 70, 71]; and 4) have a designed surface
(IL-1α and TNF- α) because of frustrated phagocytic in- charge to tune the inflammatory response (Fig. 4a) [64, 72,
teractions with cells, due to their larger size [62]. In- 73]. These nano-immunotherapeutic nanoparticles could,
creasing the hydrophobicity of the nanomaterials surface reversibly, also be used to downregulate the immune
identifies them as foreign, and potentially dangerous ma- response and inflammation, in case the QD nanotherapeu-
terials, by the immune system. This increases the tic has any adverse/side-effects due to retention of
gene-expression of pro-inflammatory cytokines [63]. Coat- over-activity. Further, the size-selected uptake of nanoparti-
ing the QD or other nanomaterial surfaces with hydro- cles acting as counter-measures for the host cells would be
philic molecules reduces the surface protein adsorption designed to counter any ROS stress, deactivation of super-
and decreases interaction with immune cells, thereby re- oxide in the host, and reduce any potential for genotoxicity
ducing immunomodulatory response. Studies on the effect from the QD therapeutic, using a coating of [Fe-S] clusters
of the surface charge have shown confounding effects with on these nanoparticles (Fig. 4a,b) [58]. Such coatings can be
other dominant physiochemical properties. Gold nanorods easily created using a hydrophobic-hydrophilic surface
with positive surface charge (amine-terminated ligands) interaction, and will be used with a small subset of FDA ap-
exhibit expression of anti-inflammatory surface antigens proved materials, like ZnO, TiO2, or silica nanoparticles.
and negatively-charged (carboxylic acid-terminated li-
gands) surfaces induced expression of pro-inflammatory Improving selective uptake in different cell-types (host
genes [64]. However, other studies have concluded that and pathogen)
negatively-charged amino acid residues can sometimes One future approach to improving QD therapeutics is
prevent uptake of long fibrillized peptide materials by targeting selective uptake between host and pathogen
antigen-presenting cells, and hence prevent presentation (Fig. 4b), as well as between different pathogens (e.g.
of epitope peptides–thereby inhibiting immune function pathogenic vs. probiotics, Fig. 4c). Size can be an im-
[65]. Overall, zwitterionic ligands or surface charges pre- portant factor in tuning uptake between host and patho-
vent accumulation/adsorption of biomolecules like pro- gens [74, 75]. By selecting for the appropriate size, a QD
teins (biofouling), thereby evading foreign-body response therapy can selectively generate therapeutic superoxide
[56, 57, 66]. These elements of immunomodulation were and induce pathogen-killing, while protecting the host
used in our QD design (small size, spherical shape, small cells using nano-countermeasures. For selectivity be-
hydrophilic ligands, and zwitterionic surface charge). By tween different types of bacteria, such as pathogenic
reducing the potential of non-specific inflammation of the strains and gut microbiota, target specificity must be
host immune system, the potential side effects of the QD considered. Reaching such targets would require the
therapeutic nanoparticles could be avoided. identification of the genomic, transcriptomic, or prote-
Other aspects of immune modulation using physio- omic factors that separate the distinct strains. QD thera-
chemical properties of nanoparticles depend on their peutics can be easily coated with peptides or DNA/RNA
molecular weight and surface roughness. The effect of molecules with appropriate target sequences (Fig. 4c)
surface topography at the nanoscale, along with surface [76–81]. Using this methodology, similar sized
chemistry was used to understand the innate immune pathogen-targeted QDs can be selectively uptaken by the
response. While surface acidity has a larger role in pathogens as a QD therapeutic, while similarly sized
immunomodulation, surface roughness directly is corre- countermeasures can be selectively transported into the
lated with enhanced matrix metalloproteinase-9 produc- probiotic bacteria, further protecting them from adverse
tion by primary neutrophils, and a decrease in the effects of the QD therapeutic. This approach can boost
pro-inflammatory cytokine secretion from primary mac- the efficacy of QD therapeutics while reducing potential
rophages [67]. This immunomodulation via surface side-effects. Importantly, the window of QD therapeutic
roughness could be attributed to a reduction in inflam- flux between host and pathogens can be further ex-
mation and increased healing on encountering rough panded to provide more immediate and effective relief
surfaces. to patients.
Based on the design rules summarized here, the adjuvant
Nano-Immunotherapeutic will: 1) be larger-size nanoparti- Conclusions
cles than QD therapeutics (< 20–50 nm), but small enough In conclusion, this review summarizes the potential, exist-
that they easily transport to reach lymph nodes [68, 69] and ing, state-of-the-art, and future outlook for an emerging
initiates/upregulates the innate immune response of the class of radical QD therapeutics. Here, we specifically
body [59], to aid the QD therapeutic and fight pathogens; sought to show several aspects of QD design, geared to-
2) be shaped as short nanorods, rather than spherical nano- wards treating MDR superbug infections. By tailoring the
particles, for preferential uptake and stronger immunomo- stimuli-triggered photochemistry, inherent materials, and
dulation [64]; 3) have induced surface roughness and chosen mechanism of action, a bottom-up rational design
Levy et al. Journal of Biological Engineering (2019) 13:48 Page 10 of 12

strategy was outlined for the QD therapeutic. This ap- Ethics approval and consent to participate
proach begins with a mechanism of redox action that tar- Not applicable.

gets a specific vulnerability in the pathogen compared to

Consent for publication
the host cells. Achieving such biological specificity is im- This is an open-access article distributed under the terms of the Creative
portant to preserve the healthy host cells and offer the saf- Commons Attribution Non-Commercial 4.0 International License (http://
est possible treatment. Selecting a redox mechanism is creativecommons.org/licenses/by-nc/4.0) which permits copy and redistribute
the material just in non-commercial usages, provided the original work is
then followed by careful material selection and 3-layered properly cited.
design to optimize safety and efficacy. The proposed ap-
proach will be bolstered by further work to develop a Competing interests
The authors declare that they have no competing interests.
nanoparticle adjuvant, such as nano-immunotherapeutics,
and nano-countermeasures for host and probiotic cells.
While the work presented here shows a design approach Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published
to radical therapy for countering adaptive resistance in maps and institutional affiliations.
bacteria, the same approach can be easily extended to a
range of different diseases (e.g. cancer), as well as to preci- Author details
1
Chemical and Biological Engineering, University of Colorado Boulder,
sion medicine. For precise treatment of diseases at the Boulder, CO 80303, USA. 2Renewable and Sustainable Energy Institute,
scale of molecular biology, healthy and diseased cells can University of Colorado Boulder, Boulder, CO 80303, USA. 3Materials Science
be distinguished from each other, and QD interactions and Engineering, University of Colorado Boulder, Boulder, CO 80303, USA.
can be tailored to exploit those differences. Using this Received: 18 February 2019 Accepted: 21 April 2019
emerging Quantum Biology approach being developed in
our group and by other researchers, a new rational design
strategy can be achieved for therapies that are dynamic or References
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