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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5346_Библиотеки_им_академика_М_И_Перельмана
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toxicity, and hypotension [30–33]. Thus, combination therapy of IL-2 and chemotherapy may be needed to result in promising effects on the tumor without having to deliver
such high and frequent doses of IL-2. Cabanes et al. investigated the combined delivery of
the immunotherapy, IL-2, and the chemotherapy drug, Dox using liposomes [9].As
reported previously, besides being a chemotherapy agent, Dox can increase the immunologic effects of immunotherapy agents. As also observed by others, Cabanes et al. also
saw that the delivery of the immunotherapy alone was not effective in large, established
tumors and therefore, there is a need for cytoreductive chemotherapy before the immunotherapy. They observed a synergistic effect between the two agents when delivered in
combination. The utilization of liposome protected the chemotherapeutic drug, Dox,
and led to less myeloid suppression usually noted with conventional chemotherapeutic
agents due to their severe bone marrow toxicity. This led to the enhancement of the
lymphocyte-activating cytokine, IL-2, which resulted in a synergistic response in tumor
eradication when the two therapies were combined.
2.5 P5 peptide
P5 peptide is a tumor antigen that can be used to stimulate the immune system by inducing cytotoxic T lymphocyte (CTL) responses in mice bearing HER2-positive tumors
[34]. It is derived from the breast cancer HER2/neu protein and is 21 amino acids in
length. P5 can be used as a peptide vaccine in cancer immunotherapy [35] . Due to its
length, the P5 peptide has several epitopes that can activate more T cell colonies, improving the immune response [36].
105Biomaterials and devices for immunotherapy
2.5.1 P5 peptide and doxorubicin
Navashenaq investigated the combination of the immunotherapy agent, P5 peptide, and
the chemotherapy agent, Dox to target myeloid-derived suppressor cells (MDSCs),
which are present in the tumor environment [10]. MDSCs can inhibit innate and
acquired immune responses. Besides having a cytotoxic activity on tumor cells,
Navashenaq also recognized Dox’s ability to increase the activity of antitumor immune
response. Dox and Doxil (liposome form of Dox) reduced MDSCs and increased
T lymphocyte activity by generating a suitable environment for efficient immunotherapy. Furthermore, the delivery of liposomal P5 after chemotherapy had induced T cell
population and cytokine secretion, which created an environment where future doses of
Dox or Doxil were able to decrease the population of MDSCs. Thus, the chemotherapy
and immunotherapy were able to boost one another.
2.6 Indoximod
The indoleamine 2,3-dioxygenase (IDO-1) pathway is an immunosuppressive pathway
that interferes in the activation of T-cells and results in the accumulation of regulatory
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T cells [11]. By inhibiting this pathway with the indoleamine 2,3-dioxygenase (IDO-1)
inhibitor, Indoximod (IND), an immune checkpoint inhibitor, an antitumor immune
response can be initiated.
2.6.1 Indoximod and doxorubicin
Immunotherapy strategies have focused on combining the immune-checkpoint blockage
with the effect of immunogenic cell death (ICD) [37,38]. Immunogenic cell death (ICD)
is a type of cell death that cancer cells face which results in the release of antigens by the
dying cancer cell and the trigger of antigen-specific immune responses [37,38]. During
this process, the dying cancer cells also upregulate the expression of tumor-associated
antigens. ICD can be triggered by anticancer drugs, radiation, or photodynamic therapy
[39,40].Luet al. utilized Dox to boost the response to the immune checkpoint inhibitor,
IND. Dox has been shown in many recent studies to cause ICD when used in small doses.
Dox has the potential to induce anticancer immune response including DC maturation
and antitumor cytokine release [41]. As seen by Lu et al. [11], the delivery of chemotherapy drug, Dox results in ICD, which can switch immune depleted to an immune repleted
microenvironment. Overall, it can boost the immune response by IND that is
coadministered with the Dox.
Besides Lu et al. [11] and Liu et al. [4], several other studies have utilized Dox to
induce ICD to enhance the response to immunotherapy; however, they have not been
discussed in this chapter as they were tested alone, and not in combination with an immunotherapy agent [40–42].
2.7 Cytosine-guanosine oligodeoxynucleotides
DCs are potent antigen-presenting cells (APC) that play a key role in immunotherapy as
they can activate T cells [43]. However, in a tumor environment, DCs show an immature
phenotype as cancer cells can impede the maturation and function of these cells [43,44].
TLR9-specific unmethylated cytosine-guanosine (CpG) oligodeoxynucleotides
(ODNs) is an immunostimulatory TLR agonist that can help DC cells mature [45].
2.7.1 Cytosine-guanosine oligodeoxynucleotides and doxorubicin
Tao et al. utilized gold nanorods to deliver CpG ODNs and Dox [12]. The CpG ODNs
mediated the production of soluble factors, such as antitumor cytokines. The combination therapy induced higher cytotoxicity than each therapy alone due to the synergistic
effect between the chemotherapy and immunotherapy, as seen by Mizuno et al. for these
two agents [46].
2.8 Tyrosinase-related protein-2
Tyrosinaserelated protein-2 (Trp-2) is a cancer vaccine that can induce the proliferation,
maturation, immunogenicity, and migration of DCs [47,48]. Cancer vaccines often have
low-response rate due to the suppression of the immune response in the tumor environment, suggesting a need to pair this immunotherapy with an agent that can help induce
the immune response [13].
2.8.1 Trp-2 and paclitaxel
Xu et al. delivered the immunotherapy cancer vaccine, Trp-2 in combination with Paclitaxel (PTX) [13]. Like Dox, a low dose of the chemotherapy drug, PTX can induce an
immune response [49]. PTX induce immunotherapy by blocking the escape of an
immune response and the maturation of DCs [50,51]. Alternatively, a high dose of
the chemotherapy can result in toxicity to immune cells, causing the impairment of
an immune response. The codelivery of the plasmid encoding Trp-2 and a low dose
of PTX induced a synergistic effect on the maturation and function of DCs.
2.9 Anti-CD326 antibody
Anti-CD326 can function as an immunotherapy by activating antibody-dependent cellmediated cytotoxicity (ADCC) and interaction of effector immune cells and cancer cells,
leading to increased phagocytosis and cytokine secretion [14].
2.9.1 Anti-CD326 antibody and sorafenib (SFN)
Shahbazi et al. delivered the immunotherapy agent, anti-CD326 in combination with the
chemotherapy drug, Sorafenib (SFN) [14]. Anti-CD326 not only functioned as immu-
notherapy, but it also played the role of a targeting agent for cancer cells and cap that
block SFN molecules within the pores of the biomaterial particles, thus preventing premature drug release.
107Biomaterials and devices for immunotherapy
2.10 Stimulator of interferon genes pathway
The activation of the stimulator of IFN gene (STING) pathway within tumor-associated
CD103
tumors into hot tumors (i.e., have an accumulation of proinflammatory cytokines and
T cell infiltration), which is vital for the success of antitumor immune responses.
2.10.1 DMXAA (STING activating agent/agonist) and SN38 (irinotecan metabolite)
Liang et al. investigated the delivery of DMXAA, a STING-activating agent/agonist, and
SN38, the active metabolite of the cytotoxic drug irinotecan [15]. Irinotecan functions as
chemotherapy by being a topoisomerase I inhibitor [52]. Besides being a chemotherapy
agent, it has also been reported to show tumor immunogenicity by inducing tumor
responsiveness to T cell-mediated antitumor immune effects [52] and increasing the
CD103 expression of DCs, which transport tumor antigens to draining lymph nodes
[53]. Liang et al. showed that DMXAA and SN38 can work synergistically to convert
+
DCs can lead to type I IFN production and the conversion of uninflamed cold
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the immunologically cold tumors into hot tumors, inducing an enhanced antitumor
immunity.
3. Nanoscale biomaterial-based strategies applied
The nanolevel/microlevel biomaterial-based strategies that were used to deliver
the immunotherapy and chemotherapy agents are discussed in the next sections. NPs
are generally defined as particles with dimensions less than 100 nm, composed of virtually any material, but unlike those used in microparticles, include semiconductors and
metals. NPs have generated significant attention as biomaterials, because of their small
size. From a purely physical standpoint, these particles are small enough to interface with
objects that control most cellular functions (e.g., 2 nm diameter DNA). NPs are also
intriguing biomaterials due to their unique size-dependent properties as the size of the
material lies between bulk and atomic composition, which imparts different physical
and chemical behavior than those usually found in their micro/macro domain counterparts. Many times the presence of a nanobiomaterial itself can enhance the therapeutic
effect of chemodrugs and immunodrugs [54,55]. Because of such interesting properties,
NPs have found application as theragnostic agents, carriers for drug delivery, and as therapeutic elements.
3.1 Polymeric and lipid nanoparticles
Organic particles are widely used for drug delivery and can be either nanoscale or microscale. There are different types and forms of organic NPs, such as lipid (i.e., liposomes,
vesicles, micelles, and microemulsions, formed by self-assembly), and polymer (or polymeric) NPs (e.g., prepared by different routes emulsion, electrospray) [56]. Polymer NPs
are made of solid polymer nanospheres, incorporating the drugs in the polymer, or
nanocapsules incorporating the drug in the core, surrounded by a polymer shell. The
drug release kinetics from these particles will depend on different properties, including
the interaction of the drug with the polymer as well as the degradation of the polymer
[57]. By using a biomaterial carrier, the drug can be protected and more precisely deliv-
ered in a better-controlled manner. Polymer and lipid NPs have been primarily used as
carriers for therapeutic and imaging agents. Therapeutic agents (e.g., small molecule
drugs, antibodies, small interfering RNAs) can be released from the nanocarriers in a controlled manner, for optimal therapeutic efficacy with minimal side effects.
3.1.1 Self-assembled amphiphilic polymeric nanoparticles
Liang et al. synthesized triblock copolymers poly(ethylene glycol)-block-poly(DTMASN38)-block-poly[2-(diethylamino)-ethyl methacrylate] (PEG-b-PSN38b-PDEA) via reversible addition-fragmentation chain transfer polymerization [15].Interestingly, the SN38-grafted PSN38 block served not only as a cleavable chemotherapy prodrug
but as a hydrophobic inner core for the hydrophobic immunotherapy agent, DMXAA to be
encapsulated. Furthermore, the carboxyl group in DMXAA can interact with the PDEA block
containing tertiary amines, thus enhancing the encapsulation of DMXAA. DMXAA was
encapsulated simultaneously during the self-assembling of the nanoparticles using a dialysis
method. Liang et al. found that the PDEA block was able to enhance the encapsulation efficiency and drug loading efficiency of DMXAA and they utilized the copolymer with the lowest polydispersity index and highest SN38 content for further studies (i.e., PS3D1@DMXAA).
3.2 Lipid-based nanoparticles or liposomes
3.2.1 Lipid-polymer hybrid nanoparticles
Yong et al. used lipid-polymer hybrid NPs (hNP) to load tin mesoporphyrin (SnMP), an
HO1-inhibitor (i.e., the immunotherapy agent) in combination with systemic DNR
[18]. The lipid layer was made of DE
out of poly(lactic-co-glycolic acid) (PLGA), which is a widely used biomaterial due to its
biocompatibility and tunable biodegradation properties. The PLGA polymeric core
allowed for the loading and release of the hydrophobic drug and the biotin- and
PEG-ylated lipid layer help to enhance the cellular uptake and permits antibody modification. The hNPs have a dual cell targeting system: (i) biotin-avidin, and (ii) antihuman
CD64-targeting single-chain antibody (scFv). The anti-CD64 antibody is effective in
human leukemia cell-targeted delivery [58]. The hNPs were targeted to CD64 + leukemia cells actively by the antibody moiety and passively to CD11b + myeloid cells,
through the phagocytic nature of the cells and negative charges of the cell surface. Higher
cellular uptake was observed with the hNPs compared to PLGA nanoparticles. Although
they observed hampered cellular uptake with higher sFVA modification, they still
decided to choose 2.5% and 5% sFVA as they expect to see more prominent effects of
this antibody in vivo.
-PEG/DPPC and the polymer layer was made
2000
109Biomaterials and devices for immunotherapy
3.2.2 Lipid nanoparticles
Lan et al. utilized pH-responsive tumor-targeted lipid NPs to locally deliver anti-PD-1
and CDDP with microneedles [6]. The DSPE-PEG-AA in the lipid NPs can bind to a
sigma receptor that is overexpressed in most tumors, thus increasing tumor targeting and
selectivity [59]. The anti-PD-1 was loaded onto the outer layer of the NPs through
nonspecific hydrophobic and electrostatic interactions. A CDDP precursor, cis-[Pt
(NH
(H2O)2]2(NO3)2, was utilized as it showed increased solubility and facilitated
3)2
the encapsulation of the chemotherapeutic drug. According to a previous study performed by the authors, in an acidic environment, such as the tumor microenvironment,
a higher proportion of anti-PD-1 dissociated from the NPs within 24 h [59]. Furthermore, CDDP in the inner layer of the NPs achieved a sustained release for 72 h. Lan
et al. demonstrated that although systemic anti-PD-1 was nonresponsive, the local
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delivery of anti-PD-1 using the lipid nanoparticles with microneedles had an enhanced
synergistic effect on the tumor and decreased the systemic cytotoxicity [6].
3.2.3 Liposome
Liposomes are very attractive biomaterial for drug delivery due to ease in preparation,
biocompatibility, and ability to load a broad range of drugs, DNA/RNA as well as diagnostic agents [60]. The surface of liposomes can be altered to attach specific ligands as
targeting agents for specific cells or tissues and can also be easily functionalized with
chemically and biologically inert polymers to increase circulation in the blood.
Lu et al. constructed a phospholipid-conjugated IDO-1 inhibitor, IND, a prodrug
that self-assembles into a lipid bilayer encapsulated nanovesicle or liposome [11]. Remote
loading of Dox into the liposome through the use of a proton gradient allows the amphiphilic drug to be imported across the liposomal membrane and results in a dual-delivery
Dox/IND carrier. The protonation of Dox leads to the formation of an intraliposomal
(Dox-NH
3)2SO4
precipitate that is not able to back-diffuse across the lipid bilayer. The
dual delivery carrier had a loading capacity (w/w) of 19.8% and 11.4%, respectively, for
IND and Dox, which is equivalent to an IND/Dox molar ratio of 4.3:1. The 100-nm
sized liposomes had a low polydispersity index and a slight negative surface charge and
were stable for up to one month in deionized water, phosphate buffer saline (PBS), and
10% fetal bovine serum (FBS)-containing RPMI-1640 medium.
Navashenaq et al. utilized different liposomes to deliver both an immunotherapy
and a chemotherapy agent. The immunotherapy agent, P5 peptide
(ELAAWCRWGFLLALLPPGIAGGGC) was covalently linked to MaleimidePEG2000-DSPE and the P5 liposomes were delivered with Doxil which is a PEGylated
liposome-encapsulated Dox [10]. Doxil has been shown to be relatively less cardiotoxic
than free Dox in seve ral tumor models regardless of tumor type and site of implantation
[61,62]. Navashenaq et al. demonstrated that liposomal P5 and Doxil resulted in greater
anticancer activity compared with free peptide and Dox, definitely emphasizing t he
importance of the utilization of biomaterials for the delivery of bioactive factors, such
as drugs, peptides, and nucleic a cids.
Cabanes et al. utilized liposomes to deliver the immunotherapy agent IL-2. Due to the
rapid clearance of IL-2, a high and frequent dose of IL-2 is often needed to achieve a therapeuticeffect;however, this is associatedwith high toxicity.Canabeset al. utilized liposomes
to improve the pharmacokineticsand immunomodulatoryactivityand reducethe toxicityof
IL-2 delivery. Two different liposome formulations, PEGylated SUVs (PEG-SUV-IL-2)
and dimyristoyl-phosphatidylcholine/dimyristoyl-phosphatidylglycerol MLV-IL-2, were
investigated in combination with Doxil. The small (diameter < 100 nm) IL-2 PEGylated
liposomes were able to boost the antitumor effect of Doxil to the same level achieved with
soluble IL-2. However, the combination of Doxil and MLV-IL-2 appeared to have lower
efficacy, probably due to the large size of the MLVs, which resulted in rapid clearance from
circulation by the reticuloendothelialsystem phagocyteswhen deliveredsystemically. Alternatively, in a regional animal model where the liposomes were delivered locally, the most
effective combination was Doxil and MLV-IL-2 liposomes. They suggested that this observationcould depend on retention and slow release of IL-2 in the peritoneal cavity due to the
inability of MLVs to enter the circulatory system or the draining lymph vessels. In contrast,
IL-2 in small liposomes or insoluble form, escaped rapidly from the peritoneal cavity. This
observation may also have resulted in enhanced uptake of MLV-IL-2 by peritoneal macrophages,compared to stealthPEGylatedSUV-IL-2.Canabes et al. demonstrated that the liposomedeliverysystemwas ableto increase the potencyof thecytokineand decrease its toxicity
compared to the soluble free form of the cytokine.
Liu et al. utilized liposomes with matrix metalloproteinases (MMPs) responsive moi-
ety as crosslinkers for PD-L1 inhibitor (anti-PD-L1 peptide) conjugates with encapsulation of low dose of the chemotherapy agent, Dox to achieve enhanced antitumor efficacy
[4]. B16F10 melanoma cells can excrete MMP-2 enzymes that could cleave the cross-
linker and release the PD-L1 inhibitor. The liposomes had pH-responsive/sensitive
moiety which can convert to a protonated state at acidic pH, resulting in the dynamic
disordering of the liposome membrane and release of the encapsulated Dox in lysosomes
which has an acidic environment as shown in Fig. 4.
3.3 Other types of nanobiomaterials delivery systems
Besides polymers and lipids, nanodelivery devices can also be made via other biomaterials, including nonmetals, such as selenium, metals, such as gold, or metalloids, such as
silicon. These inorganic NPs may have nonspherical shapes, including nanostars,
nanorods (NRs), nanoshells, and nanocages, among others.
111Biomaterials and devices for immunotherapy
3.3.1 Near infrared red-responsive gold nanorods
In biomedical applications, the most commonly investigated materials have been gold and
silver, which are created primarily through chemical reduction. Noble metals are attractive
for imaging because they exhibit surface plasmon resonance (SPR), due to their many free
electrons in the conduction band, which form a movable electron cloud. As from quantum
mechanics, electrons can also behave as waves. If the light of the same frequency as the
oscillation of the electron cloud is absorbed, the cloud resonates, producing an absorbance
signal. This signal depends on the material thickness and, in the case of nanosize materials, is
enhanced by the large fraction of atoms at the material surface. Tao et al. utilized gold
nanorods (AuNRs) immobilized with Y-shaped CpG motifs, namely, cytosine-guanosine
(CpG) oligodeoxynucleotides (ODNs), as immunotherapy [22]. The AuNRs were modified by conjugating thiol-terminated poly-(ethylene glycol) (PEG-SH), with molecular
weight (Mw) 5000) to the surface to prevent aggregation of AuNRs during the conjugation process and reduce their toxicity. The chemotherapy agent, Dox was intercalated
within the CpG ODNs and could be released from the CpG ODNs/Dox complex upon
112 Emily M. Jordan et al.
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(A)
Liberation of PD-L1 antagonist pH-responsive drug release
pH: 5.0-5.5MMP-2 digestion
(B)
D-peptide antagonist
(NYSKPTDRQYHF)
Fig. 4 (A) Schematic representation of the concept for tumor microenvironment/pH dual responsive
polymer-liposomes; (B) Acid-triggered ionization of PEG conjugated poly(β-amino ester) copolymers.
(Reprinted (adapted) with permission from Liu Y, Chen X-G, Yang P-P, Qiao Z-Y, Wang H. Tumor microenvironmental pH and enzyme dual responsive polymer-liposomes for synergistic treatment of cancer
immuno-chemotherapy. Biomacromolecules 2019;20:882–92. Copyright (2019) American Chemical
Society.)
R
N
R
N
H
DSPE-PEG
O
O
2000
O
O
O
O
O
O
N
O
N
Bu
Bu
OO
H
N
O
N
Bu Bu
H
n
n
N
O
+
H
O
O
O
O
O
O
H
N
O
OO
O
O
MMP-responsive peptide
pH-responsive polymer-PEG
O
N
O
m
R
O
H
N
O
m
R
DOX
2000
irradiation in the near-infrared (NIR), which is a high tissue penetration, nontoxic electromagnetic radiation. AuNRs are a heat source when irradiated with a laser and have tunable localized surface plasmon resonance (LSPR), allowing them to provide hyperthermal
cancer therapy [63–66]. Furthermore, the controlled release from the AuNRs can be tuned
by NIR irradiation power density and time. Without NIR irradiation, only negligible
release was observed, however, when the AuNRs were exposed to a 808 nm laser
(1.5 W/cm
2
), a burst release of Dox molecules was observed followed by continued release
and eventually leveling off. Besides the Dox, NIR irradiation could also control the release
of the CpG ODNs from the AuNRs.
3.3.2 Undecylenic acid modified thermally hydrocarbonized porous silicon
nanoparticles
The highly porous nature of silica materials, with pore diameters ranging in 2–10 nm, has
been used to encapsulate other materials, including imaging agents, drugs, DNA, and
even other nanoparticles. These materials can be slowly released at the target site to provide
a therapeutic benefit or a method of biodegradability. Shahbazi et al. utilized undecylenic
acid-modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs)
loaded with the chemotherapy drug, SFN, and surface-biofunctionalized with the immunotherapy anti-CD326 antibody [14]. Nanoporous silica platforms are associated with easily functionalized surface, high surface area, large pore volume, and high biocompatibility,
thus have been increasingly used in cancer [67–71]. Anti-CD326 not only acted as a
targeting agent for CD326 expressing cells, improving endocytosis of the NPs, it can also
act as an immunotherapy agent. Furthermore, the anti-CD326 helped prolong the release
of SFN due to its electrostatic interaction with the drug.
3.3.3 Seleniumcontaining nanoparticles
Gao et al. utilized selenium-containing NPs to deliver the chemotherapy drug, Dox [35].
Besides being the drug carrier, selenium itself provided immunotherapeutic effects and
thus, was the immunotherapy agent [7]. The release of the Dox could be controlled by
a low dose of radiation and oxidized diselenide-containing NPs to seleninic acid which
resulted in antitumor effects. Following radiotherapy, the diselenide portion in the polymer would be oxidized to seleninic acid, and the loaded drug, Dox would be released in the
cell nucleus. The NPs were functionalized with Arg-Gly-Asp (RGD) peptides that can
recognize and target the αvβ3 integrin receptor in MDA-MB-231 breast cancer cells
[72]. The functionalization decreased liver and kidney uptake and increased accumulation
in tumors.
113Biomaterials and devices for immunotherapy
3.3.4 Sulfobutylether-β-cyclodextrin (SBE)/mannosylated N,N,N-trimethylchitosan
(mTMC) polycationic polymer
Xu et al. utilized polymeric nanocomplex of PTX-encapsulated sulfobutyletherβ-
cyclodextrin (SBE)/mannossylated N,N,N-trimethylchitosan (mTMC)/tyrosinase-related
protein-2 (trp-2) DNA [13]. The gene vector,the mannosylated N,N,N-trimethyl chitosan
(mTMC)had mannose residues whichcan specifically bind to the mannose receptors (MR)
overexpressed on DCs and was used to complexwith the immunotherapy agent, tyrosinaserelated protein-2 plasmid DNA. The chemotherapy drug PTX was included insideSBE and
the anionic PTX/SBE served as a crosslinker to ionically self-assemble with the cationic
mTMC/DNA polyplexes. This system was used in combination with a microneedle for
transcutaneous vaccination. The codelivery of the DNA vaccineand adjuvant PTX resulted
in synergistic effects on DC maturation and their antigen-presenting functions (Fig. 5).
4. Introduction to micro/nanorobots
In 1966, the imagination of Isaac Asimov envisioned a fantastic journey in the
human body with vehicles driving in blood vessels. Within the last decades, scientists
have been following this dream by developing autonomous MNRs that are capable of
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Fig. 5 Schematic representation of the formation of the PTX/SBE-mTMC/DNA nanocomplexes.
(Reprinted with permission Xu J, Xu B, Tao J, Yang Y, Hu Y, Huang Y. Microneedle-assisted, DC-targeted
Codelivery of pTRP-2 and adjuvant of paclitaxel for transcutaneous immunotherapy. Small
2017;13:1700666. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
actively performing diagnostics and medical treatments [73,74]. In contrast to passive
biomaterial devices (e.g., physically inert scaffolds and microparticles/NPs), autonomous
MNRs can meet challenging clinical needs by reaching sections of the body that are difficult to access with the traditional approaches. A medical MNR is widely defined as an
untethered structure able to perform a medical procedure by accessing a target through
active propulsion [75–79]. The impact of these active devices on the biomedical field
includes, among others, targeted therapy, surgery, drug delivery, and imaging (Fig. 6).
Similar to microparticles and NPs, MNRs are made of biomaterials, but they may be
assembled to form more complex devices to provide controllable motion. The main challenge to developing MNRs is the efficient design of the propulsion system that has to
overcome the viscous forces that dominate over the inertial forces at microscopic scales
[80]. Additionally, another condition to be taken into account is the Brownian motion
that affects the directionality of movement due to the random collision of fluid molecules
with the micro/nanostructures [81].
Scientists have found nature as the primary source of inspiration to design and develop
MNRs. A first example is given by bacteria that use flagella to propel their bodies by
passively forming rotational helical bundles [82]. Other microorganismsemploy cilia
or other appendices instead to perform corkscrew-like/beating/waving movements to
penetrate fluids [81,83]. A different strategy is adopted by the Helicobacter pylori,a
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