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\begin{document}

\title{Recent progress on metal-based nanomaterials for cancer
radiosensitization}



\author[1]{Xiu Zhao}%
\author[1]{Jun Li}%
\author[1]{Qiongwei Wang}%
\author[1]{Zhenzhong Zhang}%
\author[1]{Junjie Liu}%
\author[1]{Jinjin Shi}%
\affil[1]{Zhengzhou University}%


\vspace{-1em}



  
  \date{June 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Radiotherapy is a mainstay treatment for malignant tumors in clinical.
However, enhancing radiation damage to tumor cells meanwhile sparing
normal tissues is still a great challenge in radiotherapy. Nanomaterials
with high atomic number (Z) values are promising radiosensitizers by
promoting the radiation energy deposition in irradiated tumor cells,
thus enhancing the therapeutic ratio of radiotherapy. In this review, we
described the mechanisms of high-Z element radiosensitizers and
systematically summarized the recent progress on metal-based
nanomaterials, including high-Z metal nanoparticles, metal-organic
frameworks (MOFs) and other high-Z-containing nanomaterials. Finally,
further potential and challenges in this field were discussed.%
\end{abstract}%



\sloppy


Recent progress on metal-based nanomaterials for cancer
radiosensitization

Xiu Zhao,\emph{\textsuperscript{a}} Jun
Li,\emph{\textsuperscript{a}}Qiongwei Wang,\emph{\textsuperscript{a}}
Zhenzhong Zhang,*\textsuperscript{,\emph{a,b,c}} Junjie
Liu*\textsuperscript{,\emph{a,b,c}} and Jinjin
Shi*\textsuperscript{,\emph{a,b,c}}

\textsuperscript{a} School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, China\textsuperscript{b} Key Laboratory of
Targeting Therapy and Diagnosis for Critical Diseases, Henan Province,
China\textsuperscript{c} Key Laboratory of Advanced Drug Preparation
Technologies, Ministry of Education, Zhengzhou 450001, China\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Comprehensive Summary}\tabularnewline
\midrule
\endhead
Radiotherapy is a mainstay treatment for malignant tumors in clinical.
However, enhancing radiation damage to tumor cells meanwhile sparing
normal tissues is still a great challenge in radiotherapy. Nanomaterials
with high atomic number (Z) values are promising radiosensitizers by
promoting the radiation energy deposition in irradiated tumor cells,
thus enhancing the therapeutic ratio of radiotherapy. In this review, we
described the mechanisms of high-Z element radiosensitizers and
systematically summarized the recent progress on metal-based
nanomaterials, including high-Z metal nanoparticles, metal-organic
frameworks (MOFs) and other high-Z-containing nanomaterials. Finally,
further potential and challenges in this field were
discussed.\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Keywords}\tabularnewline
\midrule
\endhead
Radiotherapy \textbar{} Nanoradiosensitizers \textbar{} High-Z metal
\textbar{} Energy deposition \textbar{} Nanomaterial\tabularnewline
\bottomrule
\end{longtable}

\section*{}

{\label{section}}

Contents

1. Introduction 2

2. High-Z metal nanoparticles for radiosensitization 2

2.1. Gold (Au)-based metal NPs 2

2.2. Bismuth (Bi)-based metal NPs 3

2.3. Gadolinium (Gd)-based metal NPs 3

2.4. Iridium (Ir)-based metal NPs 3 Page No.

3. Metal-Organic Frameworks 5

3.1. Hafnium (Hf)-based nMOFs 5

3.2. Zirconium (Zr)-based nMOFs 6

3.3. Other types of metal-based nMOFs 6

4. Other high-Z-containing nanomaterials 6

5. Conclusions and Perspectives 7

1. Introduction

As the first-line clinical management of malignant tumors, approximately
50\% of cancer patients receive radiotherapy
(RT),\textsuperscript{{[}1-3{]}}which is usually used as an adjuvant
treatment modality prior to surgery to shrink the tumor, or
postoperative prevention of residual tumor
recurrence.\textsuperscript{{[}4{]}} Radiotherapy mainly uses X-rays to
kill cancer cells. The high-energy radiation can directly cause DNA
damage, or react with water molecule to produce reactive oxygen species
(ROS), indirectly damage DNA. The accumulated DNA breaks ultimately
induce tumor cell necrosis or
apoptosis.\textsuperscript{{[}5-6{]}}Despite radiotherapy has made some
progress in suppressing tumor growth, tumor cells often show innate or
acquired resistance to ionizing radiation. For example, the soft tumor
tissues have low energy absorption coefficient, which usually requires a
high radiation dosage and cause unavoidable damage to neighboring normal
tissues, thus reducing the long-term life quality of
patients.\textsuperscript{{[}7-8{]}} In addition, the hypoxic tumor
microenvironment, strong antioxidant system in tumor cells and enhanced
DNA damage response are not conducive to effective DNA damage, which
greatly reduce radiotherapy efficiency and ultimately result in
treatment failure.\textsuperscript{{[}9-12{]}} Thus, it is crucial to
explore effective strategies for enhancing cancer radiotherapy.

Currently, impressive advances have been made in radiosensitizers for
boosting tumor radiosensitivity. Especially, due to the intrinsic
radiosensitive activities, chemical inertness, and good
biocompatibility, high-Z element-containing nanomaterials are promising
radiosensitizers and have been successfully employed for improving the
RT therapeutic efficacy.\textsuperscript{{[}13-15{]}} High-Z
radiosensitizers possess high X-ray coefficient, which is significantly
higher than that of tumor soft tissue. When tumor cells are exposed to
high-energy radiation, high-Z atoms are excited by high-energy elements
to collide due to the larger electron density. A large number of
secondary charged particles and radiated photons are released, including
Photoelectrons, Compton electrons and Auger electrons, which make a
major contribution to energy conversion and deposition in the irradiated
tumor tissues.\textsuperscript{{[}16{]}} The dose-enhancing effect
amplifies the damage of DNA directly, or producing more ROS by
dissociating water to enhance the radiation sensitivity of cancer cells.
Previously, many researchers have focused on the noble metal
nanoparticles with intrinsic radiosensitive activities and good
biocompatibility, particularly gold nanoparticles (Au NPs)-mediated
radiosensitization. With the rapid development of nanotechnology, a
large number of multifunctional high-Z element-containing nanomaterials
with synthetic tenability and drug loading capacity are continuously
reported, which broaden the horizon of this field and accelerate the
development of metal-based radiosensitizers. In this review, we
highlight the progress of metal-based nanoradiosensitizers. Based on the
structures, we divide these nanoradiosentizers into three categories,
namely, high-Z metal nanoparticles, metal-organic frameworks (MOFs), and
other high-Z-containing nanomaterials. Finally, we further discuss the
current challenges of metal-based nanoradiosentizers. We hope that this
review article can help researchers understand the latest progress of
metal-based nanoradiosensitizers and encourage all of us to make new
breakthroughs in this field in the future work.

2. High-Z metal nanoparticles for radiosensitization

So far, many high-Z metal nanoparticles have been used as
radiosensitizers to improve the efficacy of RT through a rationale of
energy deposition. They possess good chemical stability, low toxicity
and morphological diversity. Several investigations about various high-Z
metal nanoparticles have been made to improve the radiosensitivity of
tumor cells (Table. 1), including metal nanoparticles of
Au,\textsuperscript{{[}17-35{]}}Hf,\textsuperscript{{[}14, 36{]}}
Pt,\textsuperscript{{[}37{]}}Bi,\textsuperscript{{[}38-43{]}} Ir,
\textsuperscript{{[}44-46{]}}Gd,\textsuperscript{{[}47-53{]}}
Ta,\textsuperscript{{[}54{]}}Ga,\textsuperscript{{[}49, 55{]}} and
Te,\textsuperscript{{[}55, 56{]}} etc.

2.1. Gold (Au)-based metal NPs

Au nanoparticles (Au NPs) are commonly researched radiosensitizers. In
recent years, there has been a rapid development in the research on
radiation sensitization of Au NPs. The regulation of the size, structure
and surface modification of nanoparticles can optimize the efficiency of
radiation sensitization and tumor treatment to varying degrees. For
example, Coulter et al. prepared polystyrene-supported gold
nanoparticles (AuNP@PS) for increasing its stability in physiological
conditions. Compared with free Au NPs, the composite AuNP@PS showed
enhanced radiation efficiency at a dose of 4 Gy, which proved the
radiation enhancement of the polymer support
material.\textsuperscript{\textbf{{[}} 27\textbf{{]}}} Wang et al.
modified ultra-small gold nanoparticles with a tumor microenvironment
(TME)-responsive multifunctional peptide (Tat-R-EK) \emph{via} the Au-S
bonds between gold and thiol groups from cysteine on Tat peptide. The Au
NPs exhibited good stability and cathepsin B-responsive release of
Tat-modified gold nanoparticles, leading to selectively targeting tumor
cells. Such a formation improved radiotherapy efficiency by enhancing
DNA damage. Moreover, it was easily cleared by the kidney profiting from
the ultra-small size.\textsuperscript{\textbf{{[}} 26\textbf{{]}}} Liu
et al. reported an acid-triggered gold nanoparticles (GNPs) aggregation
strategy for RT enhancement. GNPs were modified with two peptides
grafting 2, 3-Dimethylmaleic anhydride, termed as GNPs-A and GNPs-B,
respectively. When arriving at the acidic tumor microenvironment (pH
6.5), the negatively charged GNPs-B was reversed to a positive charge
state, and formed a larger GNPs aggregate with the negatively charged
GNPs-A through electrostatic interaction, which promoted GNPs to
effectively accumulate at the tumor tissue and meanwhile improved
its\emph{in vivo} photoacoustic imaging ability. More importantly, the
sensitizer enhancement ratio (SER) value of the GNPs aggregation (1.73)
in MCF-7 cells was much higher than that of single GNPs (1.16), greatly
improved the radiosensitive efficiency.\textsuperscript{\textbf{{[}}
28\textbf{{]}}} In addition, Yang et al. prepared a GSH-responsive
Au-MnO Janus nanovesicle (JNP Ve) by being self-assembled with a NIR-II
dye IR1061. JNP Ve could be degraded into small Au NPs and manganese ion
(Mn\textsuperscript{2+}) in response to GSH, which not only allowed for
deep penetration of Au NPs but also produced more ROS through
Mn\textsuperscript{2+}-mediated Fenton-like reaction, significantly
enhancing RT efficacy. Meanwhile, the quenched IR1061 fluorescence was
restored for image-guided tumor detection.\textsuperscript{\textbf{{[}}
20\textbf{{]}}} As a typical example, Song et al. observed that a
multifunctional photocatalytic driven dandelion nanosystem composed of
plasma amorphous TiO\textsubscript{2} components and Au nanorods could
significantly enhance the radiotherapy effect due to the heterogeneous
structure of electron-hole pairs, which enhanced drug accumulation
through autonomous navigation.\textsuperscript{\textbf{{[}}
18\textbf{{]}}}

2.2. Bismuth (Bi)-based metal NPs

Bi-based nanoparticles are one of the hottest materials in radiotherapy.
For example, Zhao et al. provided a representative example that met both
radiosensitization and biosafety requirements. Ultra-small BiOI quantum
dots (QDs) were synthesized \emph{via} a simple two-step method. Under
X-ray irradiation, BiOI QDs with high-Z element could also generate *OH
by decomposing overexpressed hydrogen peroxide
(H\textsubscript{2}O\textsubscript{2}) for radiation enhancement. In
addition, BiOI QDs showed good biocompatibility, which were rapidly
cleared by renal metabolic pathway and showed low accumulation in liver
and spleen.\textsuperscript{\textbf{{[}} 41\textbf{{]}}} Chen et al.
synthesized plasmonic Bi/Bi\textsubscript{2}O\textsubscript{3}-x by in
situ fabrication of Bi\textsubscript{2}O\textsubscript{3}-x on
Bi\emph{via} a hydrothermal method and modified with the folate for
tumor targeting. The oxygen vacancy defects allowed
Bi/Bi\textsubscript{2}O\textsubscript{3}-x to absorb near-infrared light
for combined photothermal therapy and radiotherapy. Moreover,
Bi/Bi\textsubscript{2}O\textsubscript{3}-x showed excellent
photoacoustic imaging ability for deep
tissues.\textsuperscript{\textbf{{[}} 39\textbf{{]}}} Zhang et al.
recently reported a biomimetic RT sensitization platform by combining
cyanobacterial and 2D bismuthine. Upon the 660 nm laser and X-ray
irradiation, cyanobacteria could produce oxygen \emph{via}photosynthesis
to relieve hypoxia in tumor tissue, further amplifying Bi-mediated
radiation sensitization.\textsuperscript{\textbf{{[}} 40\textbf{{]}}}
Recently, bacteria with excellent tumor targeting have attracted wide
attention and are used as drug delivery carriers due to the easy surface
modification. As a representative example, Zhang et al. developed a
Bi\textsubscript{2}S\textsubscript{3} nanoparticles-loaded engineered
Escherichia coli MG1655 (Bac@BNP). Bac@BNP could effectively accumulate
at tumor tissues and released
Bi\textsubscript{2}S\textsubscript{3}nanoparticles in response to the
matrix metalloproteinase-2 (MMP-2). The produced cytolysin A (ClyA)
protein by Bac could regulate the cell cycle, accompanied with the
radiosensitization effect of Bi\textsubscript{2}S\textsubscript{3} for
enhanced tumor radiotherapy (Figure 1A).\textsuperscript{\textbf{{[}}
38\textbf{{]}}} Therefore, nanomaterials with Bi manifest the great hope
for radiosensitization.

2.3. Gadolinium (Gd)-based metal NPs

Similar to gold, metal nanomaterials with Gd have been developed to
promote radiosensitization. For example, by using the virus-like silica
(V-Si) as the template, Zhang et al. constructed a biodegradable
Gd-based hollow virus-like nanoparticle loaded with second near-infrared
dye ICG and then modified with cyclic RGD peptide (R\&HV-Gd@ICG). The
Gd-based nanoparticles showed excellent tumor targeting capability and
enhanced RT efficacy by producing numerous ROS and serious DNA damage.
Otherwise, its fluorescent imaging capability allowed tumors to be
visualized, which was of significance in breast conservation
surgery.\textsuperscript{\textbf{{[}} 57\textbf{{]}}} In addition, Zhang
et al. synthesized a RVG29-modified gadolinium-based biodegradable
nanocapsule for NIR-II FI/MRI-guided glioblastoma (GBM) treatment, with
PLGA as the carrier loading Gd\textsubscript{2}O\textsubscript{3}:
Nd\textsuperscript{3+} nanodots, MnO\textsubscript{2} and chemotherapy
drug TMZ. After the nanocapsule crossed the blood brain barrier and
aggregated to tumor tissue owing to the RVG29 peptide, the high-Z-based
nanocapsule released TMZ and produced O\textsubscript{2} in response to
pH for enhanced radio-chemotherapy and remarkably inhibited the growth
of the tumors.\textsuperscript{\textbf{{[}} 47\textbf{{]}}} As a
paradigm, Xie et al. developed an ultrafine gadolinium-carbon quantum
dots (Gd@Cdots) \emph{via} a hydrothermal method, which had minimal Gd
leakage and low toxicity due to the biological inertness of carbon and
rapid clearance from body. Moreover, Gd@Cdots could produce hydroxyl
radical in H1299 cells under X-ray irradiation due to the photoelectric
effect of Gd and surface catalytic effect of
carbon.\textsuperscript{\textbf{{[}} 51\textbf{{]}}} Consequently,
Gd-based metal nanoparticles can be envisioned to a certain extent as
the effective radiosensitizers to support RT.

2.4. Iridium (Ir)-based metal NPs

Iridium (Ir, Z = 77) with high stability and high biocompatibility has
hold much attention in RT field over recent decades. For instance, Liu
et al. successfully synthesized Ir nanocrystals (IrNCs) \emph{via} a
chemical reduction and were encapsulated with PEG-modified liposomes for
preventing being toxified by thiol biomolecules. According to the
photoacoustic images \emph{in vivo} , Ir@liposome showed better
accumulation and retention ability compared with Ir NPs. Moreover, IrNCs
showed catalase-mimicking activity upon NIR laser to relieve tumor
hypoxia, combined with the radiosensitization of high-Z element Ir,
greatly improved the efficacy of
radiotherapy.\textsuperscript{\textbf{{[}} 46\textbf{{]}}} Xu et al.
also reported an ultra-small Ir nanocrystals of \textless{} 5 nm, which
was decorated with RGD and TAT peptides for double targeting of tumor
cell membrane and cell nucleus. It had been demonstrated that the high-Z
element Ir effectively accumulated in the nucleus and produced extensive
DNA damage under X-rays in 4T1 cells, indicating the amazing
sensitization effect. Fortunately, Ir nanocrystals was not only a good
radiotherapy sensitizer, but also had good photothermal conversion
ability, which provides great potential for photothermal synergistic
therapy (Figure 1B).\textsuperscript{\textbf{{[}} 45\textbf{{]}}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 1} (A) Mechanism diagram of Bac@BNP-mediated
radiosensitization. Reprinted with
permission,\textsuperscript{{[}38{]}}Copyright 2022, American Chemical
Society. (B) Illustration of tumor cell membrane and cell nucleus
dual-targeting process of Ir-R/T NCs. Reprinted with
permission,\textsuperscript{{[}45{]}} Copyright 2019, Wiley-VCH.

\textbf{Table 1} High-Z metal nanoparticles for radiosensitization\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Element & Size (nm) & Shape & Surface modification & Cell line/model &
X-ray dose & Refs\tabularnewline
\midrule
\endhead
Au Au Au Au Au Au & 4.0-6.3 110 4.5 \selectlanguage{ngerman}± 0.7 \textless{} 5.5 28.2 Length:
\selectlanguage{english}~93, Diameter: \selectlanguage{english}~16 & Nanocluster Nanostar Spherical Spherical Spherical
Nanorod & Histidine Folic acid Polystyrene Peptide Peptide Amorphous
TiO\textsubscript{2} & U14 Hela DU145 LM3 MCF-7 MCF-7 & 6 Gy 6 Gy 4 Gy 4
Gy 4 Gy 4 Gy & {[}31{]} {[}22{]} {[}27{]} {[}26{]} {[}28{]}
{[}18{]}\tabularnewline
Bi & 150 & Nanosheet & Tween 20 & 4T1 & 8 Gy & {[}42{]}\tabularnewline
Bi & 100 & Spherical & Engineered bacteria & 4T1 & 6 Gy &
{[}38{]}\tabularnewline
Bi & 3 & Spherical & Tween 20 & 4T1 & 8 Gy & {[}41{]}\tabularnewline
Bi & 200 & Layered Nanosheet & Photosynthetic cyanobacteria & 4T1 & 4 Gy
& {[}40{]}\tabularnewline
Bi & 190 & Spherical & DSPE-PEG2000-folate & 4T1 & 6 Gy &
{[}39{]}\tabularnewline
Gd & 140 & Spherical surrounded by nanospike & cRGD & 4T1 & 8 Gy &
{[}48{]}\tabularnewline
Gd & 3 & Spherical & Cdots & H1299 & 5 Gy & {[}51{]}\tabularnewline
Gd & 84 & Nanocapsule & RVG29 & GL261 & 4 Gy & {[}47{]}\tabularnewline
Gd & \textless{} 5 & Spherical & - & H1299 & 6 Gy &
{[}53{]}\tabularnewline
Pt & 6.64 \selectlanguage{ngerman}± 1.3 & Spherical & BSA & 4T1 & 4 Gy & {[}37{]}\tabularnewline
Ir & \textless{} 5 & Octahedral & RGD and TAT peptides & 4T1 & 6 Gy &
{[}45{]}\tabularnewline
Ir & 3.3 & Spherical & Liposome & 4T1 & 6 Gy & {[}46{]}\tabularnewline
Te & 180 & Nanosword & GSH & 4T1 & 4 Gy & {[}55{]}\tabularnewline
Ga & 110 & Spherical & Alg & 4T1 & 6 Gy & {[}49{]}\tabularnewline
Hf & 213.2 \selectlanguage{ngerman}± 15.8 & Lamellar & MoS\textsubscript{2} & SMMC-7721 & 6 Gy &
{[}14{]}\tabularnewline
Ta & 70 & Spherical & PVP & 4T1 & 6 Gy & {[}54{]}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2} Metal-based metal-organic frameworks for
radiosensitization\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Element\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Size (nm)\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Surface modification\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Responsiveness\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Cell line/model\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
X-ray dose\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
Refs\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MC38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}70{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
212.9 \selectlanguage{ngerman}± 4.2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\selectlanguage{greek}α\selectlanguage{english}CD47\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
CT26\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}71{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80-150\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
PEG\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4T1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}72{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
190 98.1 \selectlanguage{ngerman}± 4.1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
cGAMP -\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
High phosphate -\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MC38 MC38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 Gy 2 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}75{]} {[}76{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MC38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}77{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
95 \selectlanguage{ngerman}± 18\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
KYSE 150\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}68{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
PEG\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HeLa\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}69{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
100\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
CPG\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
MC38\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}78{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
72\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
SQ20B\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}79{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Hf\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
44 \selectlanguage{ngerman}± 14\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
DDR inhibitors\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4T1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}80{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Zr\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
62\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
QU\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
PH\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
A549\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}87{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Zr Zr Th Bi\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
80 250 80 109 \selectlanguage{ngerman}± 5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
AuNPs AuNPs - -\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
High phosphate - - -\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
U87MG MDA-MB-231 CT26 TRAMP-C2\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
8 Gy 8 Gy 2 Gy 1 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}88{]} {[}89{]} {[}93{]} {[}94{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Ln\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
250\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
HeLa\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4 Gy\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
{[}95{]}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

3. Metal-Organic Frameworks

Nanoscale metal organic frameworks (nMOFs) represent a class of hybrid
materials assembled from tunable metal clusters and functional organic
bridging ligands. Over the past decade, nMOFs have emerged as a new type
of material that proposed for biomedical applications due to the
synthetic tenability, simple synthesis process, high porosity, large
surface area and good
biocompatibility.\textsuperscript{{[}58-62{]}}Notably, high-Z-based
nMOFs have shown potential antitumor ability by increasing local
radiation dose deposition and generating highly cytotoxic ROS upon x-ray
irradiation. Compared to traditional metal-based nanoradiosensitizer
(e.g., Au\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}Bi\textsubscript{2}S\textsubscript{3} and
HfO\textsubscript{2}), nMOFs present several advantages including the
improved drug loading capacity and good biodegradability, which have
emerged as a promising radiosensitizer platform. Table 2 summarized the
combination of different metal ions to form different nMOFs for
radiosensitization. Herein, we took the most popular nMOFs containing
the metal element (hafnium, zirconium, lanthanide) as paradigms to
describe a series of coordination frameworks of metal-based
radiosensitizers for improving the efficiency of radiotherapy.

3.1. Hafnium (Hf)-based nMOFs

In recent years, hafnium-based nanoscale metal-organic frameworks
(Hf-nMOFs) have received great attention in the radiosensitization field
owing to their excellent X-ray conversion and energy absorption
ability.\textsuperscript{{[}63-67{]}} For example, Cheng et al. reported
a Hf-based MOF (UiO-66-NH\textsubscript{2}(Hf)) of about 100 nm for
achieving radiosensitization, which showed a good anti-tumor
effect\emph{in vitro} and \emph{in vivo} by increasing the X-ray
absorption in tumor cells.\textsuperscript{{[}68{]}} Despite the success
of radiotherapy, the single sensitizing effect is still not
satisfactory. Multimode combined therapy has become a popular trend in
recent years. As showed in Figure 2A, Bu et al. prepared the
Fe\textsuperscript{3+}-functionalized Hf-nMOFs (Hf-BPY-Fe) for providing
the full-process radiation sensitivity by magnifying *OH formation to
obtain better radiotherapy
efficiency.\textsuperscript{{[}69{]}}Specifically,
Hf\textsuperscript{4+} in Hf-BPY-Fe (Hf-nMOFs) could produce substantial
amounts of high-energy electrons when received high-energy radiation,
which could convert H\textsubscript{2}O to *OH partially and, besides,
formed an environment of electron enrichment. The electron enrichment
environment created by nMOFs could accelerate the reduction of
Fe\textsuperscript{3+} to Fe\textsuperscript{2+}, which further promoted
the generation of *OH in the process of Fenton reaction to effectively
destroy DNA molecules. The RT enhancement mechanism of this Hf-nMOFs was
illustrated in Figure 2B. In general, this work realized CDT and RT
synergistic therapy. In addition, there were lots of works using the
strategy that combined a method based on radiotherapy and photodynamic
therapy (RT-RDT), which could significantly decrease the tumor cell
survival and delay tumor growth.\textsuperscript{{[}70-77{]}} As a
representative example, Lin et al. prepared a novel nMOF (Hf-DBBF-Ir) as
an in situ cancer vaccine by rationally integrating high-Z metal
Hf\textsubscript{6} secondary building units and photosensitizing
ligands DBBF-Ir and meanwhile loading immune adjuvant CpG \emph{via}
electrostatic interactions.\textsuperscript{{[}78{]}} Mechanistically,
after intratumoral administration, the Hf clusters could effectively
absorb X-ray to generate *OH through radiolysis and transferred energy
to adjacent photosensitizing ligands to generate
\textsuperscript{1}O\textsubscript{2}, resulting in the release of tumor
associated antigens, danger-associated molecular patterns and CpG for
antigen presenting cells (APCs) upon X-ray irradiation. In general, this
strategy of using RT-RDT effectively activated systemic antitumor
immunity through Hf-nMOFs and promoted tumor elimination. For another
example, Lu et al. constructed Hf-based nMOFs composed of Hf clusters
and DBP or TBP-based photosensitizer ligands for RT-RDT therapy, which
could efficiently eradicate primary and distant tumors under a low dose
of X-rays when combined with checkpoint blockade agent
(IDOi).\textsuperscript{{[}79{]}} In addition, Sun et al. prepared two
DNA damage repair (DDR) inhibitors-loaded nMOF (TB@Hf-BDC-PEG), which
restored the sensitivity of tumor cells to radiotherapy and improved the
apoptosis rate of tumor cells \emph{via}Hf-mediated ROS enhancement and
the block of DNA damage repair pathway of
tumor.\textsuperscript{{[}80{]}}

3.2. Zirconium (Zr)-based nMOFs

Zirconium (Zr)-based nMOFs have received great attention in recent
years.\textsuperscript{{[}81-85{]}} It is noteworthy that it has also
shown great potential in the field of radiotherapy
sensitization.\textsuperscript{{[}86{]}} Meng et al. prepared Zr-MOF
through the coordination of Zr\textsuperscript{2+} and 1,
4-benzenedicarboxylic acid and loaded with quercetin (QU) (Zr-MOF-QU).
Under tumor acid microenvironment, Zr-MOF was degraded, releasing
Zr\textsuperscript{2+}, 1, 4-benzenedicarboxylic acid and QU.
1,4-benzenedicarboxylic acid could inactive carbonic anhydrase IX by
binding to the active site of Zn\textsuperscript{2+} to relieve tumor
hypoxia, which cooperated with QU for a dual radiosensitization effects
and thus improved the efficiency of radiotherapy (Figure
2C).\textsuperscript{{[}87{]}} A hybrid nanomaterial based on Zr-based
MOF and Au NPs reported by Chen et al. significantly inhibited tumor
growth with minimal systemic toxicity, opening up a new prospect for the
next generation of therapeutic
nanomaterials.\textsuperscript{{[}88{]}}Zr-cluster and Au NPs as
radiosensitizers had high X-ray attenuation coefficients. More
importantly, the combined application of Zr and Au exerted the
catalase-Like activity to alleviate the hypoxic tumor microenvironment
by catalyzing the conversion of tumor metabolite
H\textsubscript{2}O\textsubscript{2} to O\textsubscript{2}, which
facilitated O\textsubscript{2}-dependent radiotherapy. Tian et al. also
reported core/satellite-like UiO-66/Au NPs nanohybrids for improving the
RT efficiency in the hypoxic triple negative breast cancer by dual CA IX
inhibition strategy. \textsuperscript{{[}89{]}} Once the nanohybrid
entered tumor cells, the UiO-66 matrix were decomposed by the high
concentration of phosphate, releasing p-phthalic acid, the building
skeleton of the UiO-66 MOF, to inhibit CA IX. Meanwhile, the Au NPs not
only could enhance the radiosensitivity of tumor cells but also
effectively load CA IX antisense oligonucleotide (ASO) \emph{via} Au-S
bond to knockdown CA IX. These previously integrated functional parts
cooperated with each other and played an excellent RT effect in the
hypoxic tumor bearing animal model.

3.3. Other types of metal-based nMOFs

A considerable number of nMOFs based on other metal elements have been
proven to have effective radiosensitization or synergistic killer effect
for single or multifunctional
radiotherapy.\textsuperscript{{[}90-92{]}}Thorium (Th) is a radioactive
metal element. Lin et al. reported a high-Z Th-based nMOF with
photosensitizing ligands, which could promote radiation damage of tumors
\emph{via} RT-RDT. Th-MOFs with high X-ray attenuation efficiency
promoted energy deposition and leaded to more active oxygen generation,
thus inducing significantly cell apoptosis and inhibiting tumor
growth.\textsuperscript{{[}93{]}} Bismuth (Bi) as a radiosensitizer is
also an ideal metal for building nMOFs because of the strong absorption
of X-rays. Lin et al. reported a Bi-based nanoscale metal-organic
framework.\textsuperscript{{[}94{]}} Bismuth metal-constructed nMOFs
were expected to adsorb more X-rays for enhancing the effect of RD-RDT
and triggering stronger local immune activation, which cooperated with
CBI for systemic tumor elimination. The lanthanides-based
radiosensitizer not only has natural high-Z metal but also good
biocompatibility because of the redox stability of
Ln\textsuperscript{3+} ions, which is widely used in biomedicine.
Lanthanides can interact with X-ray radiation, and their photoelectric
effect and Compton effect effectively improve the radiotherapy
efficiency. Chen et al. designed lanthanide coordination nMOFs as X-ray
responsive radiosensitizers for cancer therapy, and they could increase
intracellular ROS level according to the experimental data
showed.\textsuperscript{{[}95{]}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 2} (A, B) Illustration of the synthesis process and
full-processradiosensitization mechanism of Hf-nMOFs. Reprinted with
permission,\textsuperscript{{[}69{]}} Copyright 2020, American Chemical
Society. (C) Illustration of the radioenhancement effect of Zr-MOF-QU
NPs. Reprinted with permission,\textsuperscript{{[}87{]}} Copyright
2019, American Chemical Society.

4. Other high-Z-containing nanomaterials

Metal-phenolic networks (MPNs) are emerging versatile nanomaterials,
which are constructed \emph{via} the coordination between phenolic
ligands and metal ions. As discussed, in view of the great advantages of
metal elements in radiotherapy, a large number of MPNs based on metal
elements (e.g., Hafnium, Platinum, Gadolinium) have been prepared to
improve therapeutic benefits for radiotherapy.\textsuperscript{{[}39,
96{]}} Dai et al. have done a lot of excellent works in this field. For
example, an oxygen-enriched X-ray nanoprocessor based on the
Hf-polyphenols coordination (Hb@Hf-Ce6) was developed for improving the
therapeutic effect of RT-RDT, enhancing oxygen enrichment in tumor
microenvironment and promoting antitumor immune responses when combined
with PD-1 immune checkpoint blockade. Given the high-Z metal of Hf not
only could promote radiation dose enhancement, but also exhibited
superior photoelectric effect, which could be used as favorable light
source for RDT. Consequently, abundant ROS was generated and resulted in
tumor regression.\textsuperscript{{[}97{]}} Pt-based MPN has also been
designed as a platform for relieving tumor hypoxia, which has made good
achievements in the field of RT and sonodynamic therapy (SDT). In a
nutshell, low-intensity pulsed ultrasound (LIPUS) was performed before
radiotherapy to regulate hypoxia levels. Then the prepared PP18-Pt NPs
based on the assembly of the PEG-polyphenols encapsulated with
radiosensitizers Pt and the sonosensitizer PEG-purpurin 18 were
administrated. The radiosensitizer and sonosensitizer were
activated\emph{via} controllable LIPUS and RT, producing high
concentrations of ROS to kill tumor cells accurately as displayed in
Figure 3A.\textsuperscript{{[}98{]}} Besides, based on the robust
metal-phenolic coordination of
NaGdF\textsubscript{4}:Nd@NaLuF\textsubscript{4} and
Mn\textsuperscript{2+}, they also successfully fabricated a novel
lanthanide-doped MPN (DSPM). As shown in Figure 3B, the released
radiosensitizer and Mn\textsuperscript{2+} in response to pH sensitized
tumor cells to X-ray and promoted STING pathway activation to overcome
the radioresistance caused by the immunosuppressive microenvironment
after DSPM internalized into cells.\textsuperscript{{[}99{]}}

\textbf{Figure 3} (A) Illustration of the PP18-Pt NPs mediated
radiotherapy enhancement. Reprinted with
permission,\textsuperscript{{[}98{]}} Copyright 2022, Wiley-VCH. (B)
Illustration of the radiosensitization and immunomodulation effect of
lanthanide-doped MPN. Reprinted with
permission,\textsuperscript{{[}99{]}} Copyright 2022, Wiley-VCH.

5. Conclusions and Perspectives

In conclusion, the unique properties of nanomaterials, such as the high
surface area, stability, and tunability bring opportunities for
traditional radiotherapy. Especially, metal-based nanomaterials with the
intrinsic radiosensitive activities and chemical inertness in cellular
systems exhibit good radiosensitization effects and can be applied to
sensitize tumor cells to radiotherapy. The particle size, shape, and
surface functionalization of metal-based nanomaterials are well
manipulated with the vigorous development of nanotechnology. Therefore,
nanoradiosensitizers can be easily synthesized with desirable size and
functional modification.\textsuperscript{{[}100{]}} More importantly,
profiting from the unique advantages of nano-structure, nanomaterials
possess favorable pharmacokinetics profiles and can effectively delivery
metal-based radiosensitizers to tumor tissue \emph{via} the active
targeting or the enhanced permeability and retention (EPR) effect
mediated passive targeting. Currently, many high-Z nanomaterials have
entered clinical trials for cancer
radiosensitization.\textsuperscript{{[}101-103{]}} In particular, the
HfO\textsubscript{2}nanoparticles NBTXR3 showed encouraging radiological
and pathologic responses in patients with soft tissue sarcoma in
clinical trial.\textsuperscript{{[}104-106{]}} Therefore, metal-based
nanomaterials are promising radiosensitizers to improve the
radiotherapeutic outcome and decrease the side effects, which accelerate
the development of nanoradiosensitizers.

Despite the current some achievements, there are still some challenges
for metal-based nanoradiosensitizers, such as the potential toxicity of
nanoradiosensitizers containing heavy or toxic metals due to the
inefficient elimination from body. Compared with small molecule drugs,
nanoradiosensitizer has a longer circulation time in the body and is not
easy to degrade. Thus, the biocompatibility and long term toxicity of
nanoradiosensitizers must be comprehensively investigated before applied
to the clinic. Moreover, nanoradiosensitizer lack targeting specificity.
In the further, radiosensitizers with highly effective and low toxicity
are expected to be exploited for radiotherapy. In conclusion,
metal-based nanomaterials are promising radiosensitizers, and more
techniques need to be introduced to accelerate the development of
metal-based nanoradiosensitization for low dose radiotherapy in clinic.

Acknowledgement\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

This work was supported by the National Natural Science Foundation of
China (nos. 82172762, 21904119, 31900991, 82073395), the Innovation
Talent Support Program of Henan Province (no. 21HASTIT043), the
Postdoctoral Science Foundation of China (nos. 2020TQ0288, 2021M690140),
and the Postdoctoral Innovative Talent Support Program of Henan Province
(no. ZYYCYU202012179).

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\end{enumerate}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Recent progress on metal-based nanomaterials for cancer
radiosensitization} Xiu Zhao, Jun Li, Qiongwei Wang, Zhenzhong Zhang*,
Junjie Liu*, and Jinjin Shi*\tabularnewline
Metal-based nanomaterials amplify the damage of DNA directly, or produce
more ROS by dissociating water to enhance the radiation sensitivity by
promoting energy deposition.\tabularnewline
\bottomrule
\end{longtable}

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