Nature 2021 - Wireless On-Demand Drug Delivery

Review Article
https://doi.org/10.1038/s41928-021-00614-9
Wireless on-demand drug delivery

Seyed M. Mirvakili ✉ and Robert Langer ✉
Wireless on-demand drug delivery systems exploit exogenous stimuli—acoustic waves, electric fields, magnetic fields and elec-
tromagnetic radiation—to trigger drug carriers. The approach allows drugs to be delivered with controlled release profiles and
minimal off-target effects. Recent advances in electronics and materials engineering have led to the development of sophisti-
cated systems designed for specific applications. Here we review the development of wireless on-demand drug delivery sys-
tems. We examine the working mechanisms, applications, advantages and limitations of systems that are triggered by electric
fields, magnetic fields or electromagnetic radiation. We also provide design guidelines for the development of such systems,
including key metrics for evaluating the practicality of different smart drug delivery systems.
T
he direct administration of drugs (by, for example, injection heating in induction heating. They have been employed in medicine
or orally) has traditionally been used for acute illnesses that with different therapeutic effects such as actuating drug depots for
require an immediate dose of a drug. For chronic diseases, in vivo drug delivery, enhancing the drug molecule transport via
where a sustained systemic or targeted release is required (such as for electroporation and iontophoresis, and even directly treating cancer
diabetes, psychogenic/psychiatric diseases and cancer), long-acting tumours, called tumour-treating fields (TTFs) (Fig. 1a).
controlled release systems—including on-demand and smart drug
delivery techniques—have been developed. Drugs can be control- Actuating drug depots. Electric fields have been used to excite
lably delivered by relying on the intrinsic physical or chemical stimuli-responsive materials such as conducting polymers to
properties of the target environment to trigger chemical carriers. release therapeutic payloads6. Conducting polymers are ionically
However, on-demand drug delivery techniques, which have been and electronically conductive materials that can generate volumet-
explored over the past three decades, can offer better control over ric expansion/contraction upon electrochemical oxidation/reduc-
dosage, and the time and location of release. tion in an electrolyte12. Upon excitation with voltage, ion insertion
Passive release techniques offer a predetermined release profile or expulsion causes volumetric expansion or contraction of the
(sustained or extended) with poor control over the spatial distribution polymer structure, respectively (Supplementary Information)12.
of the drug. These approaches are useful for specific conditions (such The electrochemical reduction/oxidation enables the controlled
as disseminated diseases), but for localized diseases (such as tumours) release of the doped drug molecules (Supplementary Fig. 1a)5,13.
active and targeted release mechanisms are needed to reduce the Electroresponsive gels such as poly(dimethyl aminopropyl acryl-
non-specific toxicity of the off-target sites and enhance the overall amide) (PDMAPAA) loaded with drugs (for example, insulin) also
efficacy of the therapy. Smart drug delivery methods can provide the have been demonstrated to release the cargo when stimulated by an
necessary spatiotemporal resolution and complex release profiles. externally applied electric field14. Similarly, hydrogels prepared from
To provide such capabilities, drug carriers have been engineered to chitosan-graft-polyaniline copolymer and oxidized dextran loaded
release drugs in response to endogenous stimuli (such as pH, concen- with amoxicillin/ibuprofen have shown a controllable release rate
tration gradient, enzymes or the enhanced permeability and retention set by the applied voltage15. In these systems, the applied electric
effect) and exogenous stimuli (such as electric field, magnetic field, field also drives the charged molecules in the medium (electropho-
electromagnetic field, temperature or ultrasound) at the target site. resis), enhancing the overall efficacy14,15.
On the basis of advances in electronics, actuators and materi- By harnessing the actuation properties of the conducting poly-
als engineering, powerful wireless on-demand drug delivery tech- mers, micro-/nanovalves have been fabricated to open and close
niques have been created. These approaches exploit exogenous nanopores of the drug reservoirs made of anodized aluminium
stimuli, including acoustic waves1–4, electric fields5,6, magnetic oxide membrane (Fig. 1b)16. Unlike conducting polymers and
fields7,8 and electromagnetic radiation9–11, to trigger the drug carri- hydrogels doped with drug molecules, this technique enables a
ers. Depending on the material and design of the drug carrier, the sharp pulsatile release of drugs from large drug-depot systems16.
physiological characteristics of the target site, and the pharmaco- Conducting polymers doped with drug molecules—in the form of
kinetics and pharmacodynamics of the cargo, each of these stimuli nanodepot systems—have been shown to work with electric fields
has particular applications. In this Review, we examine drug deliv- as well (Fig. 1c)13. These nano DDSs are injected subcutaneously
ery systems (DDSs) that are operated with electric fields, magnetic and fixed in the tissue by mixing them with temperature-sensitive
fields and electromagnetic radiation. We restrict our analysis to hydrogels before injection13. To enable the delivery of larger doses,
approaches that do not require a physical medium for propagation. macroscale depot systems in the form of a film can be administered
Acoustic excitation of DDSs is also an active research field, which in vivo and removed when depleted6,14.
uses mechanical waves, such as ultrasound, to trigger DDSs, and an
analysis of such work can be found elsewhere1–4. Limitations. Application of electric fields to the depot systems is
generally via one of two routes: sharp needle electrodes inserted
Electric fields into the dermis layer (invasive), where the depot is fixed in the
Electric fields can be generated by electrostatic charges, as in par- tissue13; applying metal pads on the surface of the skin (stra-
allel plate capacitors, or time-varying magnetic fields, as in Joule tum corneum), above the depot14. The spatial arrangement of the
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. ✉e-mail: [email protected]; [email protected]
464 Nature Electronics | VOL 4 | JulY 2021 | 464–477 | www.nature.com/natureelectronics

NaTuRe ElecTRonics Review Article
a
Opening/closing pores Deformation/actuation Skin permeabilization Electromigration
and electroosmosis
Conducting polymer Drug molecule (mobile anion)
Drug molecule
E E Drug molecule E
− Water molecule
+ −
− − −
− + + +
+ + +
− +
Reduction + + + + Stratum
+ F corneum
− −
− Oxidation + + +
E − + +
+ Epidermis
− − −
+ −
−
Conducting polymer Dermis
Anion-driven actuation
b c
By electrical stimulus
PPy (DBS)
Au
Reversible
AAO Injection
Drug Electric field
subcutaneously
+ –
Open (oxidation state) Close (reduction state)
Nanoparticle
Polymer
500 nm 500 nm
– Drug
d e f
– Microcontroller Oscillating
Biological anions Neutral drug
+ and + direction of force
Biological cations Cationic drug current sensor – acting on charge
–
Neutral analyte
Rb –
Pulse + Oscillating
generator V+ Rsense Iion direction of force
acting on diploe
+ + + – Field of alternating direction

+ +
Stratum + +
corneum – Unidirectional net
+– +
force acting on
Electric field – + + –+
Epidermis +– dipole during all
–+ + cycle phases
– –
Drug molecule Dermis – + – –+
+ –+ Unidirectional net
– + force acting on
charge during all
–
+
cycle phases
Vein Artery Vein Artery
Field of alternating direction
Fig. 1 | DDSs and electric fields. a, Four mechanisms for exciting DDSs with electric fields (E). Left: electric fields open pores of a drug reservoir covered
with conducting polymers. Middle left: conducting polymer nanoparticles prepared with negatively charged drug molecules. When excited with electric
fields, the nanoparticles undergo reduction reactions that shrink the nanoparticles and release the drug molecules (other forms described in the
Supplementary Information). Middle right: application of the electric field increases the skin permeability via electroporation. Right: electric field enhances
the transportation of surface-charged small-molecule drugs by exerting force (F) on the ions. b, Electrically actuatable smart nanoporous membrane
made of polypyrrole (PPy) doped with dodecylbenzenesulfonate (DBS) for pulsatile drug release. Top: reversible change of pore size (and the drug release
rate) between oxidation and reduction states. Bottom: in situ atomic force microscopy height images corresponding to the oxidation and reduction states.
AAO, anodized aluminium oxide. c, Electric-field-responsive nanoparticles loaded with a drug. From left to right: the nanoparticle–polymer solution is
subcutaneously injected into a mouse, followed by application of a d.c. electric field to induce the release of the drug cargo inside the nanoparticles.
d, Electroporation working principle. Dielectric breakdown at the stratum corneum perforates the skin surface, increasing the permeability of the skin.
Right after, the voltage is lowered to circumvent stimulation of the underlying tissues. e, Iontophoresis working principle. A low-current signal is applied
at the skin’s surface (Iion) to transport the ions across the skin via electrophoresis/electromigration of surface-charged small-molecule drugs and then
electroosmotic flow. V+ is the applied voltage, Rsense is the sense resistor and Rb is the resistor connected to the base of the transistor. f, TTFs working
principle. Alternating current field distribution (red lines) in and around quiescent (top) and dividing (bottom) cells43. The forces exerted by the electric
field on the ions (in grey) are shown with arrows. Figure reproduced with permission from: b, ref. 16, American Chemical Society; c, ref. 13, American
Chemical Society; f, ref. 43, National Academy of Sciences.
Nature Electronics | VOL 4 | JulY 2021 | 464–477 | www.nature.com/natureelectronics 465

Review Article NaTuRe ElecTRonics
electrodes/DDSs as well as the local concentration of electrolytes generated by mobile ions in the stratum corneum29. Iontophoresis
and ionizable molecules notably affect the responsiveness of the typically works only for small molecules. However, transdermal
DDSs17. One of the challenges associated with using electric fields delivery of macromolecules up to a few kilodaltons has been shown
in biological systems is the electric double layer formation at the with this technique20.
electrodes’ surface. In electrochemically conductive electrolytes, Due to the nature of the transport mechanism in iontophoresis,
the distance at which the potential decays to 1/e of its value at the the flux of drug (often in μg cm−2 h) in the stratum corneum layer
electrode is called the Debye length (κ–1). The typical value for the scales with the electric charge transfers at the surface of the elec-
Debye length is on the order of a few nanometres for simple electro- trodes (often in mA cm−2)30. Therefore, by integrating the amount of
lytes (for example, low-concentration saltwater). In other words, in charge circulated in the circuit, the total delivered dose can be deter-
only a few nanometres from the electrodes, the potential decays to mined. For precision delivery, this task is achieved either by using a
36% of its value at the electrodes (Supplementary Fig. 1b). microcontroller (with a Coulomb counter), powered by a battery31/
Due to the high nonlinearity in the potential profile, it is difficult energy harvesting systems32, or using a battery with a known charge
to measure and control the electric field inside the tissue. Therefore, capacity (with some simple controllers)33.
it would be more accurate to measure and control the current, as Examples of iontophoresis for transdermal drug delivery include
the ratio between the applied voltage and the distance between the rapid delivery of lidocaine for local anaesthesia34, tap water for
electrodes can overestimate the electric field. Unless a reference hyperhidrosis treatment35, pilocarpine for cystic fibrosis diagnosis36,
electrode is used, constant current (galvanostatic) excitation of such fentanyl for pain relief37, acyclovir for herpes labialis treatment31 and
DDSs is a more reliable way of achieving reproducible and accurate extraction of glucose for glucose monitoring38. Aside from transder-
results for a two-electrode system. mal drug delivery, ophthalmic drug delivery with iontophoresis has
shown to be a promising approach for drug delivery. For example,
Electroporation and iontophoresis. In topical and transdermal transscleral iontophoresis of dexamethasone phosphate has dem-
drug delivery, electric fields can enhance the efficacy via electro- onstrated dramatically enhanced intraocular concentrations of
poration and iontophoresis. In electroporation, high-voltage pulses dexamethasone in ocular tissues of rabbits compared with topical
(typically >100 V) with pulse width on the order of microseconds instillation39.
to milliseconds are applied to the surface of the skin to permeabilize In a different application scheme, iontophoresis has shown
it (Fig. 1d). The process has been shown to reversibly disrupt the potential implications for treating pancreatic, breast and other solid
cell membranes (for gene transfection) and the lipid bilayer struc- tumours40,41. For example, it has been demonstrated that in vivo ion-
tures in the skin18,19. During the excitation period, electrophoretic tophoresis of gemcitabine to pancreatic cancer tumours leads to a
migration is the dominant transport mechanism. In the off-cycle, mean log2 fold change in tumour volume of –0.8 (ref. 40).
diffusion through long-lived electropores is the primary transport
mechanism (for hours). This combination increases the transder- Advantages. Iontophoresis provides notable control over the dos-
mal transport by orders of magnitude for DNA, vaccines, peptides age of delivery due to its straightforward working mechanism.
and small-molecule drugs20,21. In fact, this technique has shown Therefore, it can be used to generate complex release profiles on
some promising initial results for delivering the coronavirus disease demand without requiring complicated feedback circuits.
2019 (COVID-19) vaccine (by Inovio)22,23.
The electrical resistance of the skin (stratum corneum layer) is Limitations. Due to the slowness of the transport across the stratum
orders of magnitude higher than that of the deeper tissues. Thus, corneum (that is, minutes to hours), the small window of currents/
during excitation, there is a large potential drop across the stratum voltages (microampere to milliampere range) for safe operation and
corneum until electroporation occurs. Right after, the resistance shallow depth of delivery, iontophoresis is most effective if it is com-
drops rapidly by a large factor, which increases the potential drop bined with other methods that can increase skin permeability (for
across the deeper tissues (for example, epidermis, dermis, hypoder- example, electroporation, ultrasound)41,42. This combination possi-
mis). This potential gradient often results in the stimulation of the bly improves transdermal delivery of macromolecules or vaccines42.
muscular tissue, nerves and sweat glands. Closely spaced micro-
electrodes have been shown to resolve the issue by decreasing the Tumour-treating fields. TTFs (by Novocure) is an emerging
electric-field path length and constraining it within the stratum cor- non-invasive treatment modality that uses alternating electric fields
neum24. Controlling the current with a fast response control system/ (average 1 Vr.m.s. cm−1 and 100 to 300 kHz) (Supplementary Fig. 1c)
mechanism can prevent painful stimulation of the deeper tissues. to reduce the tumour growth rate by interfering with the cell divi-
Similar control schemes are used in the ballasts of arc lamps to limit sion process (mitosis)43. At present, this technique does not involve
the current rapidly to compensate for the rapid drop in the resis- delivering therapeutic cargos but rather achieves its therapeutic
tance (from the megaohm range to the few ohm range) of the lamp effects by using a small amplitude of intermediate-frequency elec-
after the arc formation25. tric fields alone. Regardless, we are briefly introducing this powerful
A typical topology for generating low-current and kilovolt- technique to pose possible integration of this technology with the
range-voltage pulses is high-voltage d.c.-to-d.c. converters. One wireless drug delivery techniques that we subsequently discuss in
of the low-cost (<US$450) and straightforward designs for such this Review.
d.c.-to-d.c. converters is based on an EMCO1 module and is con- In TTF therapy, the force generated by the electric field on the cell
trolled via a microcontroller (for example, Arduino)26. This design structure proteins interferes with the chromosome separation pro-
has been successfully demonstrated for exciting dielectric elastomer cess, thereby inducing cell cycle arrest and apoptosis (cell suicide)
actuators at 5 kV, 1 mHz to 1 kHz (ref. 26). of only rapidly dividing cancer cells (quiescent and non-dividing
In iontophoresis, low-voltage (typically <10 V) galvanostatic cells are unaffected) (Fig. 1f and Supplementary Fig. 1d)43,44. TTFs
(constant current) excitation of electrodes (0.5 mA cm−2) at the sur- have been demonstrated to provide powerful clinical benefit in glio-
face of the skin transports the drug across the stratum corneum layer blastoma multiforme, one of the three most common types of brain
(Fig. 1e)27. Unlike electroporation, the iontophoresis process barely tumour44. When combined with TTF therapy, an increase in sen-
alters the skin’s permeability; thus, the main driving force is elec- sitivity to chemotherapy has been shown in pre-clinical studies45.
trophoresis/electromigration of surface-charged small-molecule In addition to glioblastoma multiforme, TTFs have been shown to
drugs and then electroosmotic flow28. Molecules without sufficient suppress the proliferation of cells of different cancer types at differ-
electric charges are transported via an electroosmotic flow of water ent optimal frequencies (Supplementary Fig. 1e).

Limitations. While TTF therapy is proven to be highly effective43,44, of potential applications. Various novel designs have been explored
like many other treatments, it comes with mild to moderate adverse for delivering therapeutic cargos, as described in the recent review
effects such as scalp irritation and headache below the transducer works on this topic54,55,59; however, there is more room for integra-
array and adhesive bandage44. TTF therapy is an active field of tion with other drug delivery techniques.
research, and more on the efficacy of this technique for treating dif-
ferent tumours is a topic that yet needs to be investigated. Advantages. The mechanism of generating static and low-frequency
magnetic fields is straightforward. Moreover, compared with elec-
Magnetic fields tric and electromagnetic fields, magnetic fields have insignifi-
One of the advantages of the magnetic field over the electric field cant interactions with biological tissues making it safe for various
for application in biological systems is that it can deeply penetrate applications, including navigating magnetic-based DDSs to the
the tissue with minimal interaction with the ions (non-invasive). site of action.
These important features have enabled applications in imaging
(magnetic resonance imaging), diagnosis and targeted drug deliv- Limitations. Bulky, heavy and often expensive coils or magnets are
ery. Utilization of magnetic fields, from static and low-frequency needed to generate the required magnetic-field strengths for trig-
fields (<20 kHz) to high-frequency fields (>100 kHz), in DDSs have gering the DDSs inside the body. This size requirement for gener-
shown to be a promising technique for micro- and nanomedicine. ating the triggering stimulus limits their portability. Thus, patients
must visit medical centres to activate the DDS(s), which renders the
Static and low-frequency magnetic fields. Static and low-frequency on-demand aspect usable in only certain facilities.
magnetic fields can be generated by magnets or electromagnets.
A basic electromagnet consists of a coil with a magnetic core and a High-frequency magnetic fields. Alternating magnetic fields can
d.c. power supply. The magnetic-field strength scales with the cur- be generated by applying an alternating current through a coil or
rent passing through the coil linearly. Static magnetic fields have a rotating magnet. At high frequency (>20 kHz), magnetic-field
been used to mechanically deform soft scaffolds, infiltrated with oscillation can generate heat in metals and magnetic particles. The
ferromagnetic materials, to expel therapeutic cargo embedded heat generation occurs via different mechanisms depending on the
within their structure46,47. This technique has been shown to effec- materials’ magnetic/electrical properties and size. Metals with a
tively release therapeutic payloads on demand in vitro and in vivo grain size larger than 1 μm generate heat due to eddy current forma-
(Fig. 2a)46–48. Nevertheless, any mechanical deformation induced tion in response to alternating magnetic fields60. The eddy current
from inside or outside the body can accidentally release the content. generates a Joule heating effect, which scales with the square of the
To address this issue, liposomes (loaded with chemotherapeutic frequency (that is, f2), the square of the magnetic-field strength (that
regimens) have been engineered to release drug on demand when is, H2) and the grain diameter mean square (that is, <d2>)60. For
exposed to a low-frequency (10 kHz) alternating magnetic field49. single-domain MNPs (for example, superparamagnetic nanopar-
This engineered structure consists of chains of magnetic nanoparticles—often less than 30 nm in size), Brownian (physical alignment
ticles attached to the liposomes. Under a 10 kHz magnetic field, the of the nanoparticles) and Néel (alignment of the magnetic moment
vibration from the chains disrupts the membranes and releases the within the nanoparticles) fluctuations are responsible for heat gen-
drug to the tumour (Fig. 2b)49. eration (Supplementary Fig. 2a)60. For multidomain MNPs, hyster-
Similar to electrophoresis and iontophoresis, magnetic fields esis losses (∝ H3 and ∝ f) are the dominant heating mechanism60.
have shown the potential to enhance transdermal drug delivery. In Multiple approaches have been employed to utilize high-
magnetophoresis, a magnet (<450 mT) is placed at the skin’s sur- frequency magnetic fields in drug delivery and hyperthermia for
face to repel diamagnetic hydrophilic drug molecules across the tumour ablation7,8,61,62. One of the most promising designs uses
stratum corneum or even across cell membranes in deeper tissues50. MNPs to release therapeutic cargos from micro/nano hollow cap-
For example, it has been demonstrated that the permeability of sules (for example, liposomes)63–65 or solid particles (for example,
vascular endothelium can be increased when infiltrated with iron polymer based)66–68. For example, MNPs (such as Fe3O4, γ-Fe2O3)
oxide nanoparticles and stimulated with an external static magnetic embedded in drug-loaded biodegradable polymers, such as
field51. The force on the magnetic nanoparticles (MNPs) temporar- poly(lactic-co-glycolic acid) (PLGA), have been shown to trigger
ily disrupts the cell membranes, thus enhancing the transportation and release the cargo when excited with alternating magnetic fields
of the substances51. Unlike iontophoresis, in magnetophoresis, the (100 kHz to 200 kHz)66. When heated, the polymer network under-
drug molecules’ net charge does not affect the transportation rate. goes structural rearrangements, which increases the diffusion rate
Similarly, ions and charged particles in the tissue are not perturbed of the drug (Fig. 2d). With this technique, pulsatile release profiles
during magnetic excitation, making it a safe solution for enhancing have been demonstrated66.
transdermal drug delivery of hydrophilic drugs50. Another design has been proposed that employs thermal trig-
Aside from drug delivery, low-frequency magnetic fields have gering of lower critical solution temperature (LCST) hydrogels (for
been used to navigate micro-/nanorobots (also known as mag- example, poly(N-isopropylacrylamide) (pNIPAM)), made of net-
netic swimmers) for drug delivery and minimally invasive thera- works of crosslinked long polymer chains69, to facilitate drug release.
peutic and diagnostic medical procedures (Fig. 2c)52–54. These LCST hydrogels have a combination of hydrophobic and hydro-
magneto-responsive microcarriers can reproduce the motions of nat- philic segments in their polymer chains. At temperatures below
ural swimming microorganisms with active flagella55. The nanoro- the LCST, the hydrogels swell due to the domination of hydrophilic
bots have been shown to deliver therapeutic payloads effectively interactions with water and absorb the drug12. However, at tempera-
(for example, plasmid DNA)56 directly to the cells across the cellular tures above the LCST, the hydrogen bonds with water are broken,
membranes. Aside from synthetic magneto-responsive carriers, it and hydrophobic interactions between the polymer chains domi-
has been shown that magneto-aerotactic bacteria, Magnetococcus nate12, resulting in the deswelling of the hydrogel and the release
marinus strain MC-1—swimmers that travel naturally in the direc- of the cargo (Fig. 2e)70. This technique has been demonstrated
tion of Earth’s magnetic-field lines—can be magnetically guided for on-demand ‘burst’ release of drugs and bioactive proteins for
to deliver therapeutic cargos. They have been shown to transport stem-cell proliferation71,72.
drug-loaded nanoliposomes into hypoxic regions of tumours to A third design employs the magneto-thermal effect to open
enhance the penetration depth and the overall efficacy57,58. Magnetic the ‘gates’ or pores of drug reservoirs. The gates can be made of
guiding of micro-/nanorobots is an emerging field with a wide range thermosensitive hydrogels73,74 or just by producing defects in the

a b c
Iron oxide spheres and a drug-loaded lipsome (iii)
chemically linked into a linear assembly
100 nm
(ii) (i)
Field off Field on A
(v)
B
Oscillation of MNPs
On-command
Field off Field on drug release (iv)
d e f
B=0 B T < LCST T > LCST
Weak drug release Strong drug release
Exterior
space
1 2 3 Hydrophobic
matrix Nanogel
Pulse
MNP
Drug High concentrate B
PLGA reservoir drug
Water molecule
Macromolecule MNP
g h i
MNP Line D1
defects Vd.c. Vd.c. V d.c.
Drug
R1
T1
L D
L1
R3
D3 C1 ×6 C6
... L3
D4
R4 L2
T
T2
R2 R
C Controller
D2
Fig. 2 | DDSs and magnetic fields. a, Static magnetic-field excitation of a DDS. Top: a cylinder of a nanoporous ferrogel reduced its height by ~5% when
subjected to a vertical magnetic-field gradient of ~38 A m−2. Bottom: the corresponding macroporous ferrogel deformed by ~70% under the same magnetic
field47. b, In vitro evaluation of the RF-triggered release profile of doxorubicin from doxorubicin–nanocarrier particles. Illustration of the defects on the
liposome caused by ‘vibration’ (red arrows) of the iron oxide spheres under an RF field. c, Time‐lapse image of the pick‐and‐place micromanipulation of
a 6-μm-diameter microparticle. The circles indicate the selected microparticle. The trajectory is shown with labels (i) to (v). The stepped surface has
two levels, and A indicates the higher level and B the lower one. Scale bar, 50 μm. d, Illustration of the release mechanism. When excited with alternating
magnetic field (B), the temperature of the polymer increases, which leads to an increase in the mobility of the polymer chains. Therefore, the free volume
inside the network increases, enabling a higher diffusion rate of the macromolecules. e, For temperatures (T) below the LCST, the hydrogel swells,
while above the LCST, it shrinks and releases the cargo. f, Proposed schematic of a cross-section of the membrane, showing nanogel particles (blue),
iron oxide nanoparticles (black) and ethylcellulose matrix (light brown). Upon application of a magnetic field, the magnetic nanoparticles release heat
(red) and reversibly shrink the nanogel, enabling release of a drug (green) from a reservoir contained by the membrane. g, Local heat generation from
superparamagnetic iron oxide nanoparticles through Néel’s relaxation produces a line defect in the membrane separating melted (liquid) from solid
domains64. h, Circuit schematic of a high-frequency (100 kHz) alternating magnetic-field generator made of resistors (R1–R4), inductors (L1–L3), transistors
(T1, T2), diodes (D1–D4) and capacitors (C1–C6). Vd.c., voltage. Magnetic nanoparticles can be modelled as the secondary winding of a ‘transformer’ with the
primary winding being the induction coil. i, Circuit schematic of an electromagnet. Figure reproduced with permission from: a, ref. 47, National Academy of
Sciences; b, ref. 49, American Chemical Society; c, ref. 134, Wiley; d, ref. 66, American Chemical Society; f, ref. 74, American Chemical Society; g, ref. 64, under a
Creative Commons licence CC BY 4.0; h, ref. 60, AAAS.
membrane by locally melting/degrading it (Fig. 2f,g)64. This tech- is based on zero-voltage switching. To reduce the switching noise
nique generates a burst release, and unlike the other two designs, and the voltage/current stress on the metal–oxide–semiconductor
the drug molecules are minimally heated. Moreover, drugs over a field-effect transistor (MOSFET) during on–off transitions, soft
wide range of molecular weight (500–40,000 Da) can be delivered74. switching is used using a MOSFET with a fast body diode across
Generating alternating magnetic fields involves fast switching its drain and source (Fig. 2h,i). For higher frequencies (>500 kHz),
of a coil of an LC (inductor–capacitor) resonator. A typical topol- combining a signal generator with a radiofrequency (RF) power
ogy used for generating high-frequency (<500 kHz) magnetic fields amplifier is a better solution.

Advantages. The drug carriers with MNPs can be spatially guided Frequency (Hz) Wavelength
via static magnetic fields to increase the delivery efficacy. When at Gamma-rays 0.1 Å
the target site, the release can be either via a passive diffusion pro- 10 19
cess75 or high-frequency magnetic-field excitation of the carrier70.

The latter can be combined with hyperthermia to increase the ther- 1Å
apeutic efficacy for certain cases61. 1018

A magnetic field, at low intensities (H × f < 4.85 × 108 A m−1 s 380 nm
X-rays
) , is a non-invasive stimulus and can be generated and con-
−1 61,76
V
1 nm
trolled easily by low-cost electronics (Supplementary Information). 1017

The magnetic-field intensity scales with the inverse of the coil 450 nm
diameter60,66. As stated previously, the effective heating power per B 10 nm
mass of MNPs scales with f or f2 (depending on the materials and 495 nm 1016
Ultraviolet
its size). Therefore, by miniaturizing the coil (for example, planar G
microcoils)77 (Supplementary Fig. 2b) and exciting the coils at 100 nm
higher frequencies, a similar heating effect can be expected66. Such 570 nm 10 15
Y Visible
miniaturization can potentially enable small devices that can trigger 590 nm
1 µm
micro/nano DDSs inside the body for complications with irregu- 620 nm
O Near
infrared
lar and unpredictable occurrence of symptoms (for example, pain, 10 14
blood coagulation, psychotic disorders)66.

Infrared 10 µm
In addition to drug delivery and hyperthermia, high-frequency R
magnetic fields have been employed for the non-invasive treatment 1013
of prosthetic joint infections78 and also nuclear magnetic resonance
Thermal 100 µm
imaging79,80. Magnetically controlled DDSs is an emerging field in 750 nm infrared
nanomedicine that unveils a landscape of opportunities for imag- 1012
ing, targeted in vivo drug delivery and therapy in a multimodal Far
infrared 1 mm
fashion46,66,74,81. 1,000 MHz
1011
Limitations. At the moment, there is no direct way of measuring the UHF 1 cm
exact temperature of the MNPs inside the body. Thus, a very pre- Microwaves
cise and well-trained open-loop control system is needed to control 500 MHz 1010
Radar
MICS
the magnetic-field intensity/frequency to circumvent any excessive
10 cm
heating of the drug and the surrounding tissue and the induction MBAN
of off-target effects. By engineering the Curie temperature of the 10 9
MNPs, it is possible to set a maximum temperature limit for induc-

1m
tion heating of the MNPs and minimize necrosis and hypothermic VHF
7–13
shock to healthy tissues. 10 8
Radio, TV
It is important to note that only specific drug molecules can tol- 100 MHz FM 10 m
erate the heat generated by the MNPs. In fact, heat can have delete-
rious effects on proteins and some vaccines. Finally, the therapeutic VHF 10 7
2–6
payloads can leach or leak from the carrier due to passive diffusion
100 m
and cause complications. 50 MHz
106 AM
Electromagnetic radiation
1,000 m
Synchronized oscillations of electric and magnetic fields generate
electromagnetic waves (or their quanta, photons). Electromagnetic 10 5 Long waves
radiation covers a wide span of wavelengths, including radio waves
and microwaves, infrared, visible light, ultraviolet, X-rays and
gamma-rays (Fig. 3). These frequency bands offer unique proper- Fig. 3 | Electromagnetic radiation spectrum. In radio communication,
ties for DDSs and other medical devices, some of which have not amplitude modulation (AM) is typically used for wavelengths from 100 m
been explored yet. to 1 km. Frequency modulation (FM) is typically used around 100 MHz
frequency. The ultra-high frequency (UHF) range can span from 300 MHz
Radio waves and microwaves. RF waves are generated by the to 3 GHz. The Medical Implant Communication System (MICS) is
acceleration of charged particles in a conductor (for example, an designated for communication with medical implants. Very high frequency
alternating current in an antenna). The spectrum for radio waves (VHF) ranges from 30 MHz to about 300 MHz and has three major bands
covers as low as 30 Hz to 300 GHz with corresponding wavelengths (VHF 2–6, FM and VHF 7–13). The visible range includes red (R), orange
of 10,000 km to 1 mm, respectively. The 1 GHz to 100 GHz spec- (O), yellow (Y), green (G), blue (B) and violet (V).
trum is often defined as microwaves. There are two frequency
bands under the Medical Implant Communication Service (MICS)
approved by the Federal Communications Commission for medi- RF waves for communication and powering DDSs. By utilizing simi-
cal implants and body-worn medical devices: the 401–457 MHz lar microfabrication processes in making solid-state electronics,
band, with a total bandwidth of 29 MHz, and the 2,360–2,400 MHz microchips have been fabricated with on-chip drug reservoirs, a
band, specifically for a medical body area network (MBAN) wireless transmitter and a microcontroller to generate on-demand
(Fig. 3)82. RF waves have been utilized in DDSs in two general complex drug release profiles (Fig. 4b–e)83,84. This technique pre-
approaches. The first involves using RF waves for communication cludes micropumps and valves and works on a simple dispens-
and powering DDSs, and the second uses RF waves for exciting ing mechanism (electrothermal85 or electrochemical86 dissolution
DDSs (Fig. 4a). of the reservoirs’ membranes). Moreover, it offers a very precise

a
Clinic/ Power supply Metal NPs Not excited
physician NPs
DDS/sensor
Energy source Comm. unit µC

Oscillator
Smart switch
B RF radiation
Vth + − L1
Digital Heated NPs
∆V ≈ 1.1 V release drug
communication
L2 Joule-heated coil
+ − releases drug
2e− X = Zn, Mg 2e−
Cu2+ Rectifier
X2+ RF amplifier
Cu X Battery/
Base controller Cu + 2e → Cu(s) X(s) → X + 2e
2+ − 2+ − Sensors DDS LC tank Drug
supercapacitor molecules
and transceiver Cu2++ X(s) → X2++ Cu(s)
b c f h
Front Encapsulated 100
XTAL MATCH
10 mm
HARV
uP
Microchip
Penetration depth (cm)

d Reverse 10
IND
CAP
30 mm 1
Fat
e g
Kidney
Epoxy Bone, yellow bone marrow
Gold Brain, skin, red bone marrow
Epoxy
PMMA Drug 0.1
0.1 1 10
10 mm 5 mm Epoxy
Frequency (GHz)
i j
Reservoir Outlet Refill hole Linker
nozzle RF
Microfluidic
pump region
Nitinol-coil Gemcitabine Cetuximab
Polyimide case (C225)
cantilever
mPEG
Integrated Wireless LC-tank

capacitor 5 mm AuNP
heater/actuator
Fig. 4 | DDSs and electromagnetic fields (radio waves). a, Left: wirelessly controlled DDS with an on-board microcontroller (μC). Middle left: energy
harvesting from a galvanic cell. When a threshold voltage (Vth) is reached, the capacitor releases the energy to the DDS circuit. Middle right: wireless power
transfer via magnetic coupling between two coils (L1, L2). Right: wireless excitation of drug carriers. b, Microchip-based human parathyroid hormone
fragment (1–34) (hPTH(1–34)) drug delivery device (54 mm × 31 mm × 11 mm, length × width × height). c, Schematic cross-section of microchip assembly
showing drug release from one reservoir. d,e, Removal of an anode membrane to initiate release from a reservoir. Scanning electron micrographs of a
gold membrane anode covering a reservoir are shown before (d) and after (e) the application of +1.04 V with respect to the saturated calomel electrode
(SCE) for several seconds in phosphate-buffered saline. Scale bars, 50 μm. f,g, Demonstration of galvanic-cell-powered gastric temperature measurement,
wireless transmission and DDS. f, Images of the circuit board with each module highlighted. μP is the microprocessor, MATCH is the antenna matching
circuit, XTAL is the crystal oscillator, HARV is the energy harvesting unit, CAP is a capacitor and IND is an inductor. The encapsulated circuit board is shown
on the right. g, The drug reservoir structure and its relative size to one dime is shown. Polymethyl methacrylate (PMMA) is used to make the walls of the
reservoir. h, Penetration depth of RF fields in body tissues depending on frequency and tissue type (logarithmic scales). i, The nitinol LC wireless resonant
heater is integrated into the chip to perform cantilever actuation for drug delivery. Fabricated drug delivery chip without (left) and with (right) polyimide
casing. j, Gemcitabine-loaded, epidermal growth factor receptor (EGFR)-targeted AuNPs for drug delivery and non-invasive RF field-induced hyperthermia.
The particle shell is made of methoxypoly(ethylene glycol) (mPEG). Figure reproduced with permission from: b,c, ref. 84, AAAS; d,e, ref. 83, Springer Nature
Ltd; f,g, ref. 94, Springer Nature Ltd; i, ref. 101, RSC; j, ref. 106, Elsevier. Panel h adapted with permission from ref. 108, EMF-Portal.
spatiotemporal release profile. With this method, it has been shown by a physician, to report the device’s status and receive the dosing/
that human parathyroid hormone can be delivered daily, tested release schedule84. The silicon-based pharmacy-on-a-chip is not
for 20 days, inside the body with better release-profile consistency biodegradable and requires removal at the end of its cycle life. This
than injections84. This DDS implant has a power consumption of issue has been addressed by fabricating the chip from bioresorbable
<10 mW and runs on a battery (Supplementary Fig. 3a–c)85. It wire- materials and biological lipid membranes87–89.
lessly communicates (amplitude-shift keying (ASK) modulation Two main approaches have been proposed to eliminate the need
in the 402–405 MHz MICS band) with the base station, controlled for batteries for DDS implants: wireless power transfer and on-board

energy harvesting. One of the standard techniques in non-radiative Wavelength (nm)
wireless power transfer involves transferring energy via two induc- 200 300 400 500 600 700 800 900 1,000 10,600
tion coils through near-field inductive coupling. The device is simply
300 nm
400 nm
590 nm
630 nm
660 nm
810 nm
870 nm
970 nm
a transformer with its primary and secondary windings separated
by a short distance (Fig. 4a). This wireless power transfer mecha-
nism has been shown to enable complete wireless operation of the Stratum corneum
pharmacy-on-a-chip device discussed previously90,91. However, it Epidermis
requires precision impedance matching between the coils and is 1
extremely sensitive to the relative movement and distance between Dermis
the two coils. These shortcomings have been addressed to some 2
extent recently92,93 and should be implemented in wireless implants
Penetration depth (mm)

to be tested for real-life scenarios.
On-board energy harvesting has been shown to be a promising 3
technique for DDSs residing inside the body for prolonged periods.
Examples include harvesting the galvanic corrosion energy of metal 4
(zinc, magnesium, aluminium)–copper galvanic cells (Fig. 4f,g)94–96 Artery Vein
or harvesting high-frequency (>800 MHz) electromagnetic waves
5
(Supplementary Fig. 3d,e). The first category utilizes a recharge-
able battery in combination with a capacitor to sense/release drugs
and transmits signals wirelessly to the outside of the body94. The 6 Hypodermis
latter is still new and progress yet needs to be made for complete
human-body implementation and clinical trials. In short, it has
been previously shown that Wi-Fi signals can be harvested to power
Fig. 5 | Schematic illustration of light penetration depth as a function
up sensors97. The attenuation of high-frequency signals in tissue and
of frequency in skin tissue. Figure adapted with permission from ref. 107,
the limits set by the Federal Communications Commission for RF
American Chemical Society.
transmission power through tissue has made it difficult for imple-
mentation in DDSs for in vivo applications. A new approach has
been proposed to resolve this issue by utilizing multiple antennas advantages of operating below the optical frequency range is the
(phased arrays) to form and steer beams electronically using con- better penetration depth the microwave range offers compared with
structive and destructive interference between sources98. the near infrared (NIR)107.
RF waves for exciting DDSs. Alternative approaches to the pharmacy- Advantages. RF operated systems are easy to implement, low cost
on-a-chip technology have been proposed in which an electromag- and offer robust controllability over the release profile. Moreover,
netic wave is used to excite micropumps (for example, infusion, RF circuits can be very small and operate at low power, making
peristaltic, osmotic, displacement)99 and microvalves100 on demand them an excellent candidate for more commercially viable DDSs
to facilitate drug delivery from drug reservoirs. For example, it has and other devices for medical care.
been demonstrated that by making an LC resonator coil out of NiTi
(shape memory alloy) microwires and thermally exciting it with RF Limitations. Radio waves and microwaves interact with dipole mol-
magnetic fields, the drug can be pumped out of the reservoir on ecules (for example, water)/charge carriers and induce rotation,
demand (Fig. 4i)101. Thermal actuators are often inefficient and low vibration and/or translation in the media (for example, body fluid,
bandwidth12. Moreover, thermal excitation can have adverse effects tissues containing water and salts). These nanoscale activities gen-
on tissues if not appropriately managed. To address these issues, erate friction between molecules and/or charge carriers of other
wirelessly powered microvalves made of piezoelectric actuators atoms, thus heating up the media (Supplementary Information). To
have been proposed to release drugs on demand rapidly (similar to minimize heating of healthy tissues, the amplitude and frequency of
the ink-dispensing mechanism in inkjet printers)102. the radio waves/microwaves should be carefully chosen. As a result
The relatively large size (millimetre range) of the pharmacy- of these electromagnetic wave–matter interactions, the penetra-
on-a-chip technology and its invasive implanting process can be tion depth of electromagnetic waves is less in organs with higher
costly and uncomfortable for patients. To overcome these issues, it water or salt contents (for example, bones versus liver) (Fig. 4h)108.
has been demonstrated that it is possible to open the membranes/ Therefore, techniques, such as phased arrays, should be developed
lids by attaching ring oscillators and exciting them with 2.45 GHz to increase the wireless energy transfer with no adverse effects on
RF signals103. the healthy tissues.
At smaller scales, to enhance the penetration of the DDSs to The shape and size of the antenna dictate its optimal operating
tissues and cells, nanoparticles (for example, gold, carbon nano- frequency. For a simple antenna (for example, long wire), the length
tubes, iron-based MNPs, platinum and quantum dots) have been should be equal to the half-wavelength (λ/2) of the electromagnetic
employed104–106. Aside from carrying therapeutic cargos (for exam- wave (Supplementary Information). The higher the frequency, the
ple, antibodies) to the site of action, cancer cell ablation via heat- shorter/smaller the antenna can be designed.
ing has been demonstrated with these particles. For example, it has One of the major challenges with the implant DDSs (for exam-
been shown in a model of hepatocellular carcinoma (one of the most ple, microchip) is the requirement for the replenishment of the pay-
lethal and chemo-refractory cancers) that non-invasive RF-induced loads83,84. Currently, the whole system needs to be removed from the
hyperthermia combined with cetuximab targeted delivery of a gold body, filled with a new drug cartridge and placed back in the target
nanoparticle (AuNP)–gemcitabine conjugate is more safe and effec- site83,84. It would be useful to develop implant DDSs that can receive
tive at dosages ~275-fold lower than the current clinically used sys- the drug non-invasively or to develop approaches to refill them (for
temic dose of gemcitabine (Fig. 4j)106. example, as in an Ommaya reservoir).
The heating mechanism below the optical frequency range is
different from the surface plasmon resonance occurring in the opti- Infrared. The infrared spectrum is from 700 nm (430 THz) to 1 mm
cal frequency range and is not well understood yet107. One of the (300 GHz). Light penetration in skin tissue is maximum (~4–5 mm)

around 870 nm (NIR) (Fig. 5)109. This property has been used to make example, ruthenium complexes) trapping the drug molecules when
infrared-sensitive DDSs. Heat generation due to surface plasmon exposed to light in the visible spectrum125,126. A similar trapping
resonance (Fig. 6a,b) in metal nanoparticles (for example, gold110, mechanism has been explored with poly(ethylene glycol)–polylactic
iron oxide111, ruthenium112) has been exploited to trigger drug acid (PEG–PLA) for intravenous treatment of choroidal neovascu-
release from thermosensitive polymers. The design of such DDSs is larization with phototargeted nanoparticles127.
very similar to those discussed in the section ‘High-frequency mag-
netic fields’ with the exception that the energy-converting units are Advantages. Visible light offers similar advantages to the infrared
different (AuNPs versus MNPs) and are excited with electromag- spectrum.
netic radiation as opposed to alternating magnetic fields113–116.
Aside from directly exciting the DDSs, infrared radiation can Limitations. The visible spectrum has a smaller penetration depth
generate side reactions that can trigger the release mechanism. For compared with the infrared spectrum, but still there is a lim-
example, photosynthesizers can generate reactive oxygen species ited number of platforms that can utilize visible light as a trigger
when exposed to NIR radiation to facilitate the release of drugs for DDSs.
from DDSs (Fig. 4a,c)117–119. Like magnetophoresis and electropho-
resis, infrared radiation has been shown to enhance transdermal Ultraviolet. Ultraviolet radiation carries enough energy (~4 eV to
drug delivery via direct ablation, photomechanical waves and the 300 eV) to alter molecular bonds leading to a reconfiguration of the
photothermal effect120. molecular structure. This energy level can be harmful to the human
body as it can lead to mutation and cause cancer. However, on the
Advantages. Light has a non-invasive nature and is easy to gener- low-energy side of the spectrum and at low intensities, it has been
ate and use. More importantly, it offers high spatial resolution and shown to be useful in triggering drug release from DDSs.
temporal control, which enable sequential triggering of multiple There are a handful of polymers that reversibly shrink when
payloads with high accuracy. exposed to ultraviolet light. For example, azobenzenes undergo
cis–trans photoisomerization when exposed to ultraviolet light and
Limitations. For deep tissue, light—in the infrared, visible or ultra- contract12,128. Similarly, photoreversible [2 + 2] cycloaddition reac-
violet spectrum—is not an ideal trigger for DDSs. The photon tions in polymers containing cinnamic groups have been shown
conversion efficiency of the optical receivers on DDSs still needs to cause the polymers to contract under ultraviolet irradiation129.
to be enhanced to enable activation at low light intensities121,122. Spiropyran-based nanoparticles have been demonstrated to con-
High-power lasers and light sources can have detrimental effects on tract by about 52% (103 nm to 49 nm) when excited with 365 nm
the skin and the underlying layers121. The biocompatibility and bio- ultraviolet light (photoisomerization between spiropyran and mero-
degradability of the photoresponsive elements in the DDSs are still cyanine)130. This property has been implemented in nano DDSs to
not fully addressed for in vivo applications10. A very limited number enhance the release and tissue penetration of the drug (Fig. 6e)130.
of photoresponsive components have been explored so far, which The penetration depth of ultraviolet in the skin is less than 1 mm,
are not scalable for the real-world clinical and translational applica- which reduces the excitation rate of DDSs in deep tissues. Wireless
tions yet. Considering the open-loop nature of the technique, it is micro/nano ultraviolet sources can enable local excitation of DDSs
desirable to have some form of feedback such as imaging agents, to at the site of action by minimizing damage to the healthy tissues.
help identify the site of action (for example, tumour) and prevent
off-target damage. Advantages. Ultraviolet light offers similar advantages to the visible
and infrared spectrum plus it is energetic enough to break chemi-
Visible light. Skin penetration is less in the visible light spectrum cal bonds (for example, between a drug molecule and a carrier/
than in the infrared spectrum but has been shown to be effective nanoparticle).
enough to trigger DDSs. By tuning the diameter of AuNPs to their
plasmonic resonance wavelength (for example, 532 nm)123, it has Limitations. The high-energy property of ultraviolet also sets a limit
been shown that surface plasmon resonance can trigger the release on its application as it has detrimental effects on cells at the DNA
of drug molecules from the nanoparticles (Fig. 6d)123,124. Alternative level and can only be used in brief bursts. Moreover, it has a very
approaches involve drug release based on the decomposition small penetration depth (<1 mm). All in all, selecting the right spec-
of light-responsive organic moieties (for example, vitamin B12 trum for the phototriggered DDSs is the choice between the degree
derivatives, trithiocarbonates) or transition metal compounds (for of manipulation needed versus the penetration depth in the tissue.
Fig. 6 | DDSs and electromagnetic fields (infrared to gamma). a, Left: NIR-triggered O2 releasing and enhanced photodynamic therapy mechanism.
Middle left: light-triggered surface plasmon heating of AuNPs releasing the attached drug molecules. Middle right: light-triggered molecular
reconfiguration of the drug carriers enables the release of the payload. Right: light-induced cavitation. For example, light-induced singlet oxygen generation
cavitates the liposomal membrane and releases the drug. b, Graphical illustration of plasmons in bulk gold (left) and NPs (right). Left: bulk plasmons can
be excited by an electron beam (bottom), while propagating surface plasmon polaritons (PSPPs) are excited by the evanescent field of light (top). Right:
localized surface plasmons (LSPs) are excited by light propagating in free space or dielectric media (top). The LSP in AuNPs can be modelled, as a first
approximation, like a spring-mass harmonic oscillator, where the free-electron density is the equivalent of the mass (bottom). c, Schematic illustration of
NIR-triggered O2 releasing and enhanced photodynamic therapy (PDT) mechanism in a metal–organic framework nanoplatform for highly efficient PDT
against a hypoxic tumour. d, Visible-light-triggerable aptamer/hairpin DNA–AuNP (apt/hp-AuNP) conjugate for targeted drug delivery. Aptamer
Sgc8c is a short DNA sequence that can target protein tyrosine kinase 7 (PTK7). e, Scheme of the photoswitching of spiropyran and its nanoparticulate
formulation. Top: structure and photoisomerization reaction between spiropyran (SP) and merocyanine (MC). Bottom: scheme of photoswitchable SP/
DSPE–PEG lipid hybrid nanoparticles (NPHs). DSPE, 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine. f, Schematic illustration of gene silencing and
cancer-cell-killing by X-ray-triggered liposomes. This liposomal delivery platform incorporates verteporfin (VP) and AuNPs. Two types of cargo, antisense
oligonucleotide and doxorubicin, are respectively entrapped inside a liposomal middle cavity for demonstration of in vitro gene release and in vivo drug
delivery. Figure reproduced with permission from: b, ref. 135, IOP; c, ref. 118, Elsevier; d, ref. 123, American Chemical Society; e, ref. 130, National Academy of
Sciences; f, ref. 132, under a Creative Commons licence CC BY 4.0.

X-ray. X-ray is most often used in radiation therapy for treating can- incorporating AuNPs and verteporfin photosensitizer into drug-
cer (for example, skin, brain, lung, prostate, breast)131. Owing to its loaded liposomes132. Under 6 MeV X-ray radiation, verteporfin
high radiation energy, 124 eV to 124 keV (10 pm to 10 nm—atomic generates singlet oxygen, disrupting the liposomal membrane and
scale), and considerable penetration depth, X-ray has been widely releasing the cargos (Fig. 6f)132.
used for imaging of inner organs in the body. X-rays are generated
via the interaction of highly accelerated electrons with electrons Advantages and limitations. Owing to the X-ray radiation’s consider-
of tungsten atoms within a vacuum tube. Aside from radiotherapy able penetration depth, this technique offers prospects for wireless
and imaging, recently, it has been proposed to use X-rays to trig- triggering of nanodrug carriers in deep tissues. However, the nega-
ger drug release in tumours to achieve synergistic effects com- tive side-effects of X-ray radiation on healthy tissue must be consid-
bined with the standard radiotherapy132. The technique involves ered to maximize its benefits.
a
Photodynamic therapy Surface plasmon heating Molecular reconfiguration Liposomal cavitation
Light Light Light
Photosynthesizer
Heating Heating Cavitation
Ultraviolet
AuNPs AuNPs
Visible
Oxygen
AuNPs Singlet
Drug molecules
O2 release Photosynthesizer oxygen 1O2
Singlet oxygen 1O2
b λ c
+
+ +
d<λ
LSP Laser
Membrane
– – degradation
–
– + – T
PSPP –
– –
– –
–
O2
+ release
e Laser
+ + + + +
– – – – – –
O2
+ + +
Bulk plasmon
+ + Enhanced
Normoxia Hypoxia PDT 1
O2
d
532 nm laser
f
Nucleus
Nucleus
PTK X-ray
7
PTK
7
hpDNA Sgc8c Doxorubicin
e
Ultraviolet
Cancer therapy
Visible or
in dark
Spiropyran (SP) Merocyanine (MC)
Gene silencing
Ultraviolet (365 nm)
Visible or
in dark
SP NPHs MC NPHs
Targeted liposomes loaded with VP and gold in a lipid

DSPE–PEG MC SP Drug bilayer would release gene or drug under X-ray radiation

Gamma-rays. Gamma-rays are emitted by the change in the energy The biodegradability rate of the drug carrier is most important
state of the nucleus of atoms, which is distinct from X-rays, where when carrying potent payloads, or small payloads that need to travel
the transition in energy states of electrons is responsible for radia- long distances to reach the site of action. If the DDS degrades while
tion. Gamma-rays are generated through radioactive decay of still containing the payloads, it can cause severe adverse drug reac-
nickel-56 and cobalt-56 and have energy levels from a few kiloelec- tions. In the other extreme case, if after releasing all payloads on
tronvolts to 8 MeV (wavelengths of atomic nuclei scale). Due to the demand the DDS does not degrade (for example, the silicon micro-
extremely high energy levels of gamma-ray radiation and its adverse chip), it can cause long-term complications, especially when the
effects on biological tissues, at present, no DDS has been made for device needs to be replaced frequently.
use with gamma-rays. However, recently it has been shown that
gamma-rays can be used to sterilize nano DDSs (for example, chi- Off-target adverse effects. Every DDS has pros and cons, including
tosan microparticles, liposomes, niosomes, sphingosomes), with the effects the drug and the stimulus can have on off-target tissues/
almost no side-effects, before administration133. environments. For example, excitation of DDSs with magnetic/elec-
Compared with electric and magnetic fields, electromagnetic tromagnetic fields can be harmful to those who use a pacemaker.
radiation can be collimated easily (for example, lasers, with reflec- Potent chemotherapeutic agents can be detrimental to healthy tis-
tors) to increase the radiation intensity without increasing the sues if the DDSs release inaccurate doses or release at unnecessary
input power to the source. However, electromagnetic radiation is time intervals. Multistimuli platforms—DDSs that can be triggered
absorbed by the skin at specific wavelengths, generating adverse with multiple endogenous and/or exogenous stimuli—can enhance
effects on healthy tissues. the localization of the therapy. However, they are still at an early
stage and more research is needed to validate their advantages over
Design guidelines the already established single-stimulus techniques.
Depending on the application of DDSs, different metrics are used Some stimuli, such as ultraviolet and X-ray, are known to dam-
to evaluate their suitability. These metrics are more meaningful for age tissues and, for that reason, are often used in radiation therapy
DDSs that are tested in vivo. While there are many elegant designs for cancer. It has been shown that synergistic effects can be obtained
in the literature reporting high-efficacy DDSs tested in vitro, their when ultraviolet- or X-ray-triggerable DDSs loaded with chemo-
performance must be evaluated in vivo to obtain a realistic opin- therapeutic agents are used with radiation therapy (Fig. 6f). We
ion about their pros and cons. The most important metrics that believe there is plenty of room for using this strategy with other
are commonly used to evaluate the practicality of a DDS include stimuli discussed in this Review.
the following.
Scalability for mass production. There is a rich literature on proof
Biocompatibility. The safety and biocompatibility of some of the of concepts for various elegant DDSs that are fabricated from com-
elements used to make remotely triggerable DDSs (for example, plex/long reaction routes and exotic precursors7,70. However, their
photosynthesizers, thermoresponsive hydrogels, photoswitchable scalability for mass production needs to be studied further.
organic molecules) need to be studied further for application in the
human body. Several biocompatible platforms such as silicon/gold/ Outlook
platinum/titanium components and biodegradable polymers (for The field of drug delivery is interdisciplinary, incorporating poly-
example, PLGA, PLA, polycaprolactone (PCL)) have been proven mer chemistry, medicine, materials science, biology and—increas-
to be safe for in vivo applications. However, there is a limited num- ingly—electrical engineering. As highlighted here, electrical
ber of functionalities that they can offer. It is still a grand challenge engineering can play an influential role in the design of smart and
to make remotely triggerable DDSs that are fully biocompatible and functional DDSs, and considering recent advances in nanoelectron-
biodegradable. ics, increased integration of electronics into smart DDSs can be
Aside from biocompatibility with the body environment, the DDS expected in the coming years. Electronically powered, fully control-
should also be compatible with the drugs. Otherwise, unwanted reac- lable DDSs could provide dynamic control over release profiles, as
tions might occur that damage the DDS and cause complications. well as the timing of the release. Such systems could, for example,
synchronize release-time intervals of chemotherapeutic regimens
Effective cycle life. One of the most important parameters is the with the circadian rhythms of the patient. Adding sensing capabili-
length of time that a wirelessly triggerable DDS can operate inside ties to the DDSs could also potentially enable fully automated DDSs
the body. This metric relies on three parameters: triggerability of that can sense the blood content, detect the change in the parameter
the DDS as a function of time and number of successive excita- of interest (sugar, for example), and trigger the system to release
tions, biodegradability rate of the drug carrier and the amount of the appropriate payload. The functionality of DDSs in delivering
payload(s) released in every excitation. therapeutic payloads to the target sites is of great importance in
The number of times a DDS can be triggered without losing evaluating efficacy, but medication compliance and adherence are
performance should be much larger than the number of excitations other factors that influence overall therapeutic efficacy. The devel-
it takes to fully deplete the DDS. In choosing the right stimulus opment of low-cost and highly functional DDSs that can reside in
for triggering DDSs, it is important to consider whether multiple the body for extended periods (including life-long) could enhance
DDSs are placed in close proximity. In this case, it is necessary to public health and help reduce healthcare costs in the long run. The
use stimuli with high spatial resolution and temporal control (for use of digital and electronic systems is among the most promising
example, light). approaches to achieving such goals.
Biodegradable DDSs release passively, setting the basal release
rate, until the trigger increases the release rate. For certain applica-
Received: 14 October 2020; Accepted: 16 June 2021;
tions, passive release can be harmful. A silicon chip DDS addresses Published online: 22 July 2021
this issue but is not biodegradable. On the contrary, the biodegrada-
tion rate of polymer-based platforms can be adjusted depending on
the intended effective cycle life but at the cost of required higher References
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Review Article

Wireless on-demand drug delivery

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