Nanomaterials as Novel Biomarkers for Cancer Nanotheranostics: State of the Art

Abstract

Cancers including hematological malignancies and metastatic solid tumors are one of the life-threatening diseases to the general population, which have become a heavy burden for patients and their caregivers physically and mentally. Despite the great progression in preclinical and clinical studies, effective implementation strategies are urgently needed to optimize the advancements in cancer diagnosis and treatment. State-of-the-art updates have indicated the application of multifunctional nanotheranostics as an emerging diagnostic and therapeutic tool for cancer management. Herein, this chapter displayed the literature and description of various nanomaterial-based noninvasive diagnostic and therapeutic approaches for cancer administration from the view of nanomaterial classification and nanomaterial-based application in nanotheranostics as well as the promising perspectives and grand challenges in nanomedicine. Collectively, this review will provide overwhelming new references for cancer supervision and benefit the medical and pharmaceutical practice in the field of nanotheranostics.

1. Introduction

Cancers with high heterogeneity and uncontrolled cell division are notoriously hard to conquer and have emerged as one of the leading causes of death worldwide with a prevalence of over 10 million mortalities annually [1, 2]. Over the years, a certain number of investigations have been accomplished to figure out the fundamental pathogenesis and the concomitant treatment regimens including surgery, oncolytic virotherapy, radiotherapy, chemotherapy, photothermal therapy, RNA vaccine, peptide-based neoantigen vaccine, hormone therapy, and immunotherapy [3, 4, 5, 6]. Generally, surgery (e.g., robotic surgery, laparoscopic rectal surgery) has been considered the best option for localized cancers without transfer and diffusion, which usually works in combination with chemoradiotherapy for the eradication of residual cancerous cells [7, 8]. Chemoradiotherapy has become a notable and synergistic anticancer treatment for a variety of locally advanced solid tumors through a rationale of two concepts (chemotherapy, radiotherapy) of in-field cooperation and spatial cooperation but inevitably increases microbiota resistance and damage to normal tissues [9, 10, 11]. Current progresses have also highlighted the potential of anticancer immunotherapy including immune cells and checkpoint inhibitors for the significant clinical benefit [3, 4, 9, 12, 13, 14]. Meanwhile, despite new insights into RNA vaccine-derived immunity in melanoma treatment, those cancer vaccine trials in the late-stage patients with various treatment-refractory tumors have not been successful [6, 15, 16, 17]. Therefore, in overall consideration of the shortcomings (e.g., off-target effects, severe toxicity, drug delivery barriers, and graft-versus-host disease), the aforementioned treatment regimens fell short of expectation in cancer administration [1, 3, 12, 18, 19, 20].

State-of-the-art updates have highlighted the feasibility of nanomaterials as promising agents for cancer diagnosis and therapy based on the rapid progress of nanobiotechnology and clinical biomedicine [21, 22, 23]. To date, multidisciplinary research has further highlighted the superiority of the newly emerging bidimensional (2D) nanomaterials in multiple physicochemical properties and ultrathin layer-structured topology for theragnostic nanomedicine such as graphene and its derivatives, transition metal carbides (MXenes), hexagonal boron nitrides (h-BN), black phosphorus (BP), transition metal dichalcogenides (TMDCs), palladium (Pd) nanosheets, and transition metal oxides (TMOs) [24, 25, 26, 27].

Therefore, this chapter principally focused on the current progress in nanomaterials for cancer nanotheranostics including the classification of nanomaterials (e.g., inorganic nanomaterials, organic nanomaterials, organic-inorganic hybrid nanomaterials), nanomaterials in cancer diagnostics (e.g., contrast agents for in vivo imaging, signal modes for in vitro diagnostics) and cancer treatment (e.g., cancer phototherapeutics, photothermal therapy, photodynamic therapy, cancer immunotherapy, combined therapy), and ultimately summarized the opportunities and challenges of nanomaterial-based cancer nanotheranostics. Collectively, the nanomaterial-mediated nanotheranostics had constituted a promising area of oncology theragnostics.

2. Nanomaterials and classification

Nanoparticles, with a size ranging from 1 nm to 100 nm, reveal many unique properties in terms of light, heat, electricity, magnetism, sound and chemistry, and in particular, the “hobby” of lodging with tumor cells endow themselves with enhanced permeability and retention (EPR) effect [28, 29].

Generally, nanomaterials are categorized as inorganic nanomaterials, organic nanomaterials, and organic-inorganic hybrid nanomaterials, which have been extensively developed for tumor diagnosis and treatment based on their unique biofunctions and biomedical characteristics [30, 31]. Among them, inorganic nanomaterials are the earliest studied and most widely used biomaterials in clinical oncology treatment including noble metal nanoparticles, metal chlorocarbon nanomaterials, magnetic nanoparticles, and quantum dots. These inorganic nanomaterials usually possess a series of excellent properties such as strong near-infrared light absorption capacity, high photothermal conversion efficiency, easy preparation, and modification, which thus enable the applications in fluorescence imaging, photoacoustic imaging, or nuclear magnetic resonance imaging [32]. Organic nanomaterials can be divided into organic small molecule nanomaterials and organic polymer (polymeric) nanomaterials, which are employed in the area of bioluminescent probes, photothermal therapy, and drug carriers due to their unique properties (e.g., diverse structure, easy to cut, low assembly cost) [33]. Organic-inorganic hybrid nanomaterials not only possess improved stability and biocompatibility of inorganic nanoparticles but also reveal enhanced hardness and strength of organic matrix materials, which thus have a wider range of applications over organic and inorganic materials [34].

Of note, the pathological structure of tumor tissue has the characteristics of low pH value, hypoxia, new blood vessels, and lymphatic vessels in the microenvironment owing to the anatomical structure and physiological function are quite different from normal tissues [35, 36]. Owing to the aforementioned characteristics, tumor tissues can be specifically targeted by nanoparticles in order to achieve an efficient and accurate diagnosis and treatment.

3. Contrast agents for in vivo imaging

As one of the most life-threatening diseases worldwide, the morbidity and mortality of cancer are increasing year by year [37]. Traditional diagnostics mainly focus on pathological examinations and endoscopic examinations, which often cause certain trauma to the patient’s body. In recent years, clinical imaging diagnoses of solid tumors have mainly relied on computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound (Figure 1). However, these methodologies are not safe and efficient enough for monitoring the changing microstructure of tumors due to the ionizing radiation damage, insufficient resolution, and lack of targeting. Therefore, it is urgently needed to develop a new type of nanomaterial contrast agent with high efficiency, accuracy, low toxicity, and side effects for clinical tumor diagnosis and treatment, which thereby benefits the enhancement of sensitivity and accuracy of tumor diagnosis [38, 39].

Figure 1.

Schematic illustration of the biofunction of nanomaterials.

3.1 Metal nanomaterials and CT

CT is a noninvasive imaging technique that uses X-rays, γ-rays, or ultrasound to scan a certain area of the human body in order to achieve differential diagnosis via the variations in signal absorption among different types of cells [40]. In recent years, the application of based-metal elements (e.g., gold, bismuth, tantalum, and ytterbium) of nanomaterials as contrast agents has been extensively reported (Table 1).

Metal	Contrast agent	Characteristics	Application
Gold	Based on gold nanoparticles and its derivatives	Stability, biocompatibility, enhanced CT contrast, safety, high X-ray absorption, Expensive	Solid tumors, blood-pool imaging capability
bismuth	Bi2S3 nanoparticles	Biocompatibility, high X-ray absorption, safety, long blood half-life, cost-effective	Solid tumors; lymphoscintigraphy, cartilage imaging
tantalum	Tantalum oxide nanoparticles and its derivatives	Biocompatibility, enhanced CT contrast, safety, cost-effective	Lymphoscintigraphy, cartilage imaging
ytterbium	Based on ytterbium nanoparticles and its derivatives	Biocompatibility, X-ray extinction ability, enhanced CT contrast	Blood-pool imaging capability
lutetium	Based on lutetium nanoparticles and its derivatives	Biocompatibility, enhanced CT contrast	Metabolic contrast imaging

Table 1.

CT imaging system based on metal nanomaterials.

Generally, differing from the iodine-containing nanoparticle imaging system (denoted as “soft particles”), metal-based compound nanoparticles (denoted as “hard particles”) manifest more reliable stability in the body and are easier to bypass the body’s immunity system barrier to reach the tumor lesions and improve imaging efficiency. Meanwhile, these metal elements exhibit higher density and atomic numbers for effective absorption of X-rays, which makes up for the insufficient contrast ability of iodine as a contrast agent and sharply reduces the X-ray radiation dose of patients during imaging. In addition, the surface of metal-based nanoparticles is easy to be modified by physically or chemically methods, which enhances the targeting and versatility of CT imaging probes in clinical applications [22]. For instance, Luo et al. reported the accumulation of prostate-specific membrane antigen (PSMA) targeted AuNPs in prostatic cancer revealed a size-dependent pattern [41]. Shao et al. developed a novel Bi2S3 nanoparticle coated with a hyaluronic acid (HA)-modified tantalum oxide (TaOx) nanoshell (Bi2S3@TaOx-HA) for multimodality breast cancer diagnosis, which manifested excellent biocompatibility, photothermal transducing performance and computed tomography imaging capacity [42]. Instead, the carboxybetaine zwitterionic-coated tantalum oxide (TaCZ) nanoparticle CT contrast agent was reported with greater contrast enhancement compared with a conventional iodinated contrast agent in swine models [43]. Notably, thrombocytopenia and neutropenia in patients could be predicted after 177Lutetium-lilotomab satetraxetan treatment based on the SPECT/CT-derived absorbed dose [44].

3.2 Magnetic nanomaterials and MRI

MRI is a type of noninvasive tomographic imaging, which is used to obtain electromagnetic signals from the body and reconstruct human body information. The combination of nanomaterials and MRI technology can improve the sensitivity and accuracy of MRI, and in particular, the iron-based magnetic nanomaterials with various shapes and sizes are extensively explored. For example, superparamagnetic iron oxide (SPIO) nanoparticles serve as an ideal MRI contrast agent and have been approved for clinical application attributed to their unique properties such as dual-function angiography, longer half-life in blood, specificity reticuloendothelial system, venography effect, and in vivo tracking of cell labeling [45].

Meanwhile, various raw materials with outstanding characteristics have also been reported such as high magnetic torque, saturation, and coercivity. For example, Wang et al. synthesized the Au-Fe₃O₄@PDA-PEG-DTPA-Gd hetero-nanostructure with reasonable biocompatibility and high photothermal conversion efficiency, which was adequate to completely inhibit the growth of MDA-MB-231 tumor in vivo [46]. Xu et al. generated the tumor-targeted NPs (DOX@Gd-MFe₃O₄ NPs) by combining Gd-doped mesoporous Fe₃O₄ nanoparticles with doxorubicin (DOX), which exhibited good colloidal dispersity, superior magnetic properties, superior NIR photothermal conversion, and NIR-triggered DOX release [47]. Additionally, amine-functionalized CuFeSe₂-NH₂ nanoparticles were reported with specificity against 4 T1 and HepG₂ cells due to the multifaceted signatures including water solubility, cytocompatibility, hemocompatibility, and biosafety [47].

3.3 Isotope nanomaterials and PET

Fluorodeoxyglucose is the main medium in PET, which functions as a critical element in various metabolisms and accumulates in high-metabolic tumor tissues rather than in low-metabolic normal tissues [48]. In recent years, radionuclide-labeled nanomaterials in PET have become a research hotspot for cancer diagnosis and monitoring due to their preferable properties such as high sensitivity and precise spatial quantification capabilities (Table 2). For example, Song et al. took advantage of the ¹³¹I-labeled copper sulfide-loaded microspheres for the treatment of hepatic tumors via hepatic artery embolization [49]. Peng et al. confirmed the excellent safety profile and favorable pharmacokinetics of a self-assembling [⁶⁸Ga] Ga-NOTA supramolecular dendrimer nanosystem for PET imaging, which was more competent for the detection of imaging-refractory low-glucose-uptake tumors compared to the clinical ¹⁸F FDG [50]. Co-injection of CBT-NODA-⁶⁸Ga with CBT-NODA or CBT-NODA-Ga has been reported for the enhanced micro-PET tumor imaging in mice via accelerating the synthesis of hybrid gallium-68 nanoparticles in furin-overexpressing cancer cells [51].

Methods	Labeling	Characteristics
Chelating reactions	DOTA/NOTA/NODA	High costs, low efficiency, poor labeling stability
Direct bombardment of nanoparticles by proton or neutron beam	16O (p, α) 13 N; 18O (p, n)13 N; 165Ho (n, γ)166Ho	Rapid preparation, short-half-life radionuclide-labeled nanomaterials, unstable bioactive molecules on the surface
Direct synthesis with radioactive and non-radioactive materials	^64Cu, ^68Ga, ^18F	Highly stable radiolabeled nanomaterials
Radiolabeling without chelating agent	Superparamagnetic iron oxide nanoparticles (SPION)	Rapid preparation, high specificity and labeling rate, limitation in combining radionuclides with nanoparticles

Table 2.

Methodologies of radionuclide-labeled nanomaterials for PET.

4. Application of different signal modes in diagnostics in vitro

Nanomaterials can be used to generate different types of detection signals, amplify the intensity of detection signals, and simplify the detection process attributed to their unique optical properties (e.g., magnetic, electrical, and thermal), which thus have broad application prospects in vitro diagnosis upon nucleic acids, proteins, small molecules, bacteria and viruses (Figure 2). Currently, the applications of fluorescent signals, surface-Raman signals, magnetic signals, electrochemical signals, color signals, and thermal signals of nanomaterials are the most representative signal detection modes for diagnostics in vitro (Table 3). For instance, Liu et al. generated a versatile nanoprobe based on reduced graphene oxide (rGO) and nucleic acid (DNA) nanoprobe, which provided a general sensing platform for highly sensitive imaging of dual miRNAs in living cells [52]. Lin et al. developed a microfluidic biosensor for Salmonella detection based on viscoelastic inertial microfluidics for separating magnetic bacteria from unbound magnetic nanoparticles (MNPs) and enzyme catalytic colorimetry for amplifying biological signals [53]. Compared with the unmodified electrode, a glassy carbon electrode (GCE)-based ultrasensitive electrochemical biosensor modified by a unique sandwich-like nano-Au/ZnO sol-gel/nano-Au compound revealed high absorbability and surface activity, good electro-conductivity, and biocompatibility [54].

Figure 2.

Nanomaterial-based tumor diagnostics.

Signal types	Carriers	Target objects	Applications	Principles
Fluorescent signals	Quantum dots, graphene oxide, gold nanoparticles	Nucleic acid, protein, influenza virus antigen, intracellular virus titer	ELISA immunoassay, DNA microarray	Fluorescence encoding capability, energy transfer (FRET) detection
Raman signals	Carbon	Nucleic acid, protein, tumor cells, bacteria, virus and tracer of small molecule drugs in living cells	Analysis method (molecular structure)	The surface plasmon resonance effect of metal nanoparticles to enhance Raman signals
Magnetic signals	Magnetic nano-particles	Proteins, nucleic acids, tumor cells and bacteria detection	Bio-assay reagent	The surface of microspheres is modified by magnetic nanoparticles
Electrochemical signals	Gold nanoparticles or carbon nanotubes	DNA, protein, virus, bacteria	Bio-affinity electrochemical sensor	Sandwich-like structure of using nanoparticle-labeled surface-binding analyte
Color signals	Gold nanoparticles	DNA	Nucleic acid-colorimetric detection	Coupling of DNase and gold nanoparticles
Thermal signals	Gold nanoparticles	Influenza A, malaria, clostridium	Thermal contrast signal detection	Near-infrared detector

Table 3.

Application of representative signal detection modes for diagnosis.

5. Nanomaterials in cancer treatment

For decades, multifaceted treatment options for cancer such as surgery, chemotherapy, radiation therapy, pharmacotherapy, targeted therapy, cellular therapy, and combined therapy have been developed, yet the clinic prognosis of tumor patients is still unsatisfactory [4, 55, 56]. For instance, despite the great efforts focused on cancer drug discovery pipeline (e.g., PD1/PDL1 axis), the undesirable outcomes and burdensome expenditures of pharmacotherapy alone or in combination with other strategies including nanomaterials still need to be overcome [57, 58].

5.1 Nanomaterials in cancer chemoradiotherapy

Radiotherapy, including external radiation and internal radiation therapy, is one of the main treatments and adjuvant therapy for oncologic treatment, which can efficiently reduce the misery and pressure as well as affect the tumor environment (TME) but may cause a severe untoward effect upon patients [59, 60]. Chemotherapy is treatment with specific drugs to obliterate or shrink the metastatic cancer cells before or after surgery. The chemotherapy drugs can be divided into antimetabolites (e.g., 6-mercaptopurine), alkylating agents (e.g., cyclophosphamide), topoisomerase inhibitors (e.g., Topotecan), and anticancer antibiotics (e.g., Bleomycin), which mainly function by suppressing cell division of both cancer cells and normal cells in the body (e.g., bone marrow, gastrointestinal mucosa) and thus cause adverse effects.

State-of-the-art updates have reported the involvement of unidimensional (1D) and bidimensional nanomaterials (2D) with aromatic ring carbon particles in cancer chemoradiotherapy and device fabrication based on the unique nanosheet structures, tunable chemical composition, the large surface areas, surface functionalization, minimal thickness, and other extraordinary physicochemical properties (Figure 3) [61, 62]. For drug delivery via encapsulation or covalent linking or surface adsorption, nanoparticles are loaded with biomolecules and chemotherapeutic drugs based on noncovalent bonding (e.g., van der Waal’s force, hydrophobic interaction, π–π stacking) [63, 64].

Figure 3.

Categories of nanomaterial-based tumor therapeutics.

To date, a variety of 2D nanomaterials with potential of acting as drug delivery nanoplatforms have been synthesized by different methodologies, which attract the tremendous interest of investigators in the field such as transition metal dichalcogenides (TMDC), layered double hydroxides, transition metal dichalcogenides, nitrides and carbonitrides, metal-organic framework nanosheets, graphene and its derivatives, and black phosphorus nanosheets [61, 65]. In particular, those with unique X-ray attenuation and easily tunable properties such as graphene and TMDCs are adequate to be harnessed for radiotherapy or phototherapy of cancer.

5.2 Nanomaterials in cancer phototherapeutics

Phototherapeutics, a next-generation therapeutic modality, is a type of photo-responsive regulation of biological function and relative stimuli-responsive features, which thus supplies promising prospective for promoting the accuracy and efficacy of cancer treatments via producing reactive oxygen species (ROS) by photosensitizers and eliminating cancer cells by specific wavelength light irradiation [66, 67]. Generally, phototherapeutics can be divided into three typical categories including photobiomodulation (PBM), photodynamic therapy (PDT), and photothermal therapy, which are widely applied to cancer administration such as colorectal cancer, head and neck cancer, breast cancer, and colorectal cancer [68, 69]. However, ineffective treatment of cancers by PDT can be caused by specific tumor environments and even hindered by the deep tumor cells [70].

To date, increasing literatures in the cutting-edge research area have turned to phototherapy combined with various nanomaterials in cancer therapy. Of them, carbon-based materials such as graphene and carbon nanotubes have attracted attention in the field of cancer phototherapy worldwide attribute to their unique physical and chemical properties including large surface area, thermal conductivity, and electrical properties [68]. Additionally, several kinds of nontoxic photosensitizers involved in phototherapy are also functionalized on the aforementioned carbon-based nanomaterials. Current research has also highlighted the potential role of stimuli-responsive nanomaterials (PNMs) with characteristics of responding to endogenous pathological changes for smart tumor-specific phototherapeutics [66]. For instance, Fu et al. took advantage of the porous shuttle-shape platinum methylene blue (IV-Mb) coordination polymer nanotheranostics-loaded 10-hydroxycamptothecin (CPT) for synergistically enhancing the in situ mitochondrial reactive oxygen species (ROS) and highly efficient tumor ablation by phototherapy, which was regarded as a promising method for synergistic oncotherapy [70]. Furthermore, a TME-sensitive oxygen-dual-generating nanosystems named MnO₂@Chitosan-CyI (MCC) has been developed to decrease the level of glutathione (GSH) and relieve environmental tumor hypoxia, which reveals synergistic effects with PDT in cancer treatment by triggering an acute immune response and reducing tumor metastasis [67].

Of note, the chemodynamic therapy (CDT) based on photothermal-enhanced Fenton has also attracted considerable research attention in the field, and the nanocatalyst-based strategy with high specificity and limited side effects has also emerged as a promising therapeutic option for the in-situ treatment of various cancers [71]. For instance, a number of multifunctional nanomaterials (e.g., metal oxide- or metal-sulfide-based nanocatalysts) have been manufactured to trigger the reaction within the TME and generate highly cytotoxic hydroxyl radicals as well [71].

5.2.1 Nanomaterials in cancer photothermal therapy (PTT)

Nanomaterial-based PTT has been recognized as a promising therapeutic modality for whole-body anti-tumor immune response and tumor ablation in the tumor microenvironment [72, 73]. Recently, Yang et al. took advantage of the magnetite nanomedicine in the administration of lung cancer and reported the synergistic effect with hyperthermia and chemotherapy, which collectively suggested the designed SPIO@PSS/CDDP/HSA-MTX nanoparticles with good biocompatibility and stability as powerful candidate nanoplatform for future antitumor treatment strategies [55]. Meanwhile, gold-nanobranched-shell-based vehicles and near-infrared nanomaterial-liposome hybrid nanocarriers (NIRN-Lips) with dual superiorities such as higher tumor permeability, enhanced photoluminescence, stimulus-responsive drug release, better tumor-targeted drug delivery, and anti-tumor efficacy have been applied in cancer PTT and chemo-photothermal therapy as well [23, 74, 75]. Collectively, it is of paramount importance for the future improvement of photothermal therapy (PTT) via incorporating drug conjugates and polymer linkers with the surface of nanomaterials, which will further enhance the multiplexing capability and surface functionalization of nanomaterials as well as the advanced cancer imaging and therapies [61].

5.2.2 Nanomaterials in cancer photodynamic therapy (PDT)

Photodynamic therapy (PDT) is a noninvasive form of therapy that combines both photophysical and photochemical processes, which has emerged as a promising therapeutic modality for cancer and nononcological diseases of various types and locations [59]. Differ from the aforementioned chemoradiotherapy, the third-generation photosensitizers of PDT are more affordable and dispense with hospitalization. PDT mainly functions via the activation of photosensitizers with an applicable wavelength of light and the upregulation of transient concentration of reactive oxygen species (ROS) accumulated at tumor sites, which has emerged as an important therapeutic option in oncology [76]. In recent years, PDT has attracted widespread attention as a highly selective and noninvasive approach for various cancer treatments, and in particular, the carrier nanoparticles with additional active supplementary and complementary roles [77]. However, PDT has inherent defects in treating deep tumors due to the insufficient luminous flux and limitation in approved drugs as well as the inevitable occurrence of peripheral tissue damage [59]. Additionally, due to the unique tumor microenvironment, the PDT-induced immune responses upon cancers are generally mild and thus not sufficient to ultimately eradicate metastatic cells as well [67].

The combination of nanomaterials with photosensitizers can further potentiate the efficiency and selectivity of PDT and help eliminate the side effects [78]. Current investigations have illuminated the practicality of utilizing the persistent or scintillation luminescence nanoparticles (e.g., porphyrins) with conjunctive photosensitizers for photodynamic therapy, which is adequate to enhance the effectiveness of X-ray-based ionizing radiation and minimalize the potential damage to healthy cells [79]. For example, Wang et al. developed novel biphasic and bimetallic Rh-based core-shell Au@Rh-ICG-CM nanostructures with good biocompatibility and photoacoustic imaging properties for the treatment of hypoxic tumors in combination with PDT and verified the synergistic enhancement upon oxygen generation from the endogenous hydrogen peroxide in cancer [80].

Generally, nanoparticles as delivery vehicles in PDT can be functional and classified into active participants and passive carriers during photosensitizer excitation [76]. Meanwhile, a series of oxygen-evolving agents (e.g., perfluorocarbon, catalase, HbO₂) for self-supplying oxygen and Manganese dioxide (MnO₂)-based nanoparticles with high reactivity toward H₂O₂ have been incorporated into the PDT nanosystems [67]. Distinguish from the nonbiodegradable carriers with extraneous functions, active nanoparticles can be mechanistically subclassified and divided into self-illuminating nanoparticles, upconverting nanoparticles, and photosensitizer nanoparticles [81]. Nevertheless, the cancer regions deep in the body and the deficiency of the second-generation PDT nanoparticles still remain the major obscure challenges before the adoption in large-scale clinical application [67]. In consequence, there is an urgent need for the development of intelligent nanosystems capable of functioning in the TME and enhancing the therapeutic efficacy of PDT for deep cancers.

5.3 Nanomaterials in cancer immunotherapy

The complex orchestration of cancer cells with tumor immune microenvironment results in the emergence of novel immunotherapy-based treatment regimens in patients [3, 14]. Immunotherapy such as immune checkpoint blockade and adoptive cell infusion has turned into a powerful clinical alternative for cancer administration attributes to their durable responses in hematologic malignancies and multiple metastatic solid tumors [82, 83, 84, 85]. Generally, cancer immunotherapy functions mainly via stimulating or training the inherent immunological systems and thus benefits the recognition, attack, and eradication of cancer cells with minimal damage to normal cells as well [13, 83]. Notably, cancer immunotherapy (e.g., natural killer cells, chimeric antigen receptor transduced T cells, cytotoxic T-lymphocyte antigen 4, programmed cell death-1) might cause unique toxicity profiles or an insignificant spectrum of immune-related adverse events (irAEs) differ from the toxicities of chemoradiotherapy and phototherapeutics depending on their mode of action [82, 86]. Worse still, despite the potentially favorable outcomes for advanced-stage patients such as complete cures and long-term survival, it is reported that cancer immunotherapy only works well in a relatively small subset of patients [87]. For example, Gong et al. recently reported the prominent challenges to the further broad implementation of T-cell-based immunotherapies including insufficient expansion, decreased cellular vitality in vitro, and trafficking of T cells into solid tumors [88].

In recent years, nanoparticle-based nanomedicine has revealed dramatic progress in the fast-rising field of cancer immunotherapy and has boosted therapeutic outcomes. Nanomaterials with unique chemical and physical features offer advantaged therapeutic platforms for photo-induced hyperthermia and cancer immunotherapy by turning the “cold” nonimmunoresponsive cancers and metastases into the “hot” immuno-responsive lesions [87, 89]. Moreover, nanomaterial-based nanomedicines can also be employed to target the tumor immune microenvironment, potentiate antigen presentation, trigger the release of danger-associated molecular patterns, inhibit immunosuppressive cells, and thus boost the therapeutic outcomes of cancer immunotherapy [87]. Of note, the fourth generation of biomaterials including nanomaterials is expected to stimulate a more specific cellular response and a more accurate control of sophisticated immunomodulation to the implants or cancers [90]. Collectively, nanomaterials after rational designation are uniquely suited to overcome the aforementioned challenges in cancer immunotherapy.

5.4 Nanomaterials in combined therapy of cancer

Due to the aforementioned deficiency in cancer treatment, investigators have turned to exploring the feasibility of combining nanomaterials with other strategies (e.g., surgery, chemotherapy, radiotherapy, immunotherapy) for increasing the coordination of treatment effects as well as reducing the side effects [77, 91, 92]. Different from monotherapy, combination therapy for cancer patients usually provokes a good response to tumor surveillance and clearance [93]. Of note, Wang et al. recently summarized the ferroptosis-inducing nanomedicine by combining ferroptosis with nanomaterials, the conventional treatment, and emerging therapy for cancer therapy, yet most of the ferroptosis inducers such as system Xc-inhibitors (e.g., erastin and sorafenib) and GPX4 inhibitors (e.g., RSL3 and altretamine) had not been clinically approved due to nonspecific distribution, poor solubility, and unpredictable side effects [1, 94].

In the last years, a variety of 2D nanomaterials (e.g., ceramic-based biomaterials and 2D MXenes) with prominent physiochemical properties and specific surface properties (e.g., protein corona formation, unique planar structure, and chemical modification) have been explored in cancer management in combination with surgical treatment, radiotherapy, chemotherapy, photothermal therapy, photodynamic therapy, chemodynamic therapy, radiodynamic therapy, and immunotherapy [84, 95]. For example, current achievements in the combination therapy of glioblastoma with nanocarriers have demonstrated increasing benefits against the disappointing clinical outcomes and existing challenges such as blood-brain barrier (BBB), tumor heterogeneity, glioma stem cells, drug efflux pumps, and toxicity, which are particularly formidable challenges in developing cancer therapeutics [63, 64]. In addition, nanocarrier-based combination therapy has been supposed to ensure the targeted colocalization of drugs into the tumor sites and facilitate sequential drug exposures and the synergistic drug ratio [64]. As reviewed by Zhao et al., numerous nanoformulations (e.g., Doxil, Abraxane, and DaunoXome) were not only adequate to load hydrophobic and hydrophilic drugs and prolong the half-life of diagnostic or theranostic agents, but also could reduce the toxicity of the parent compound and thereby ameliorate its therapeutic index [64].

6. Discussion and conclusions

Cancers of various kinds remain a core challenge and life-threatening disease taking millions of peoples’ lives as well as exacerbating the quality of life of the survivors [2, 13]. Despite the inspiring advances in the cancer treatment paradigm, high mortality and the concomitant toxicities of traditional therapies result in a significant challenge to adherence and tolerability of patients, and in particular, the severe adverse effects and toxic effects of chemoradiotherapy and phototherapeutics on patients cannot be neglected [96, 97]. Therewith, pioneering clinicians and researchers turned to alternate treatment regimens with a complete response and minimum side effects during cancer treatment. Among them, anticancer nanomedicine has been studied for over 30 years and a handful of formulations have been approved for clinical purposes, which has revolutionized the remedy of several advanced-stage tumors [30, 98]. For example, Chen et al. reported a novel and low-cost modality for augmented efficacy upon cancers via a combination of in vivo luminescent nanoparticle agent-based radiation and photodynamic therapies [79]. Meanwhile, chemodynamic therapy (CDT) in combination with photothermal therapy (PTT) and multifunctional nanomaterials has also been utilized to enhance therapeutic efficacy in cancer theragnostic, which also provides more effective efficacy when compared with monotherapy [71]. Despite the unique physical and chemical properties including targeting specificity and profound stability, the application of nontoxic nanomaterials coated with appropriate structures and biocompatibility for in vivo imaging is of great importance for clinical purposes. Moreover, considering the influence of the large size of nanomaterials for localization in tissues, nanoparticles should be degraded into the essential components before they can be excreted via metabolism or the kidneys.

Nevertheless, the tumor microenvironment as well as the toxic and side effects of current therapeutic regimens still remain the major obstacle to be overcome [3, 58, 60, 72]. For this purpose, great efforts have been expended on the modification of the physicochemical surface properties of nanomaterials with increased complexity and adaptability for the more sophisticated immunomodulation against various tumor cells in the past decades [90, 93]. For instance, a series of novel nanomaterials based on the surface modification of MXenes for combination therapy with magnetic resonance (MR), magnetic resonance imaging (MRI), or computed tomography (CT) have been manufactured such as Nb₂C nanosheets with polyvinylpyrrolidone (PVP) decoration, PEGylation assembled into Ti₃C₂ nanosheets, Ta₄C₃ nanosheets modified with the soybean phospholipid (SP), Ta₄C₃ nanosheets coupled with Fe₃O₄ nanoparticles, Ti₃C₂ MXene attached to mesoporous silica nanoparticles (MSNs) [99].

To date, topographical modification of nanomaterials has become an attractive and expanding field aiming to dissect the sophisticated diversity of synergistic interactions between surface nanotopography and cancer cells, and thus holds the promising prospect for solving the long-lasting challenges in cancer nanotheranostics [84, 90]. Notably, self-assembled nanomedicines with unique and versatile features have been extensively explored for dealing with the malignancy and heterogeneity of tumors, which are designed to enhance antitumor immune responses via a series of immuno-potentiating biofunctions and controlled pharmacokinetics in the tumor regions [98]. However, considering the heterogeneity of tumors and inefficiency of nanoparticle loading and releasing, it remains challenging to ensure agents specifically targeting cancer cells and alleviating collateral toxicity to healthy tissue. Most of all, despite the plethora of information on cell-surface interaction and nanofabrication at the research level, there is still a long way to obtain more advanced nanopatterning techniques and transform the academic knowledge into commercial technologies or clinical practice [90, 100]. Nanomaterials are acknowledged as advantaged sources for tumor surveillance and elimination. Distinguish from our previously reported biomaterials and various counterparts of immune cells such as T cells, dendritic cells, natural killer cells, and Treg cells, the nanomaterial-based nanomedicine efficaciously fulfills the function of combating transformed hematological malignancies and metastatic solid tumors. Moreover, considering the inherent properties, nanomaterials are “off-the-shelf” products satisfying the clinical demand for large-scale manufacture for cancer diagnosis and treatment.

Acknowledgments

The coauthors thank the members of the Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, The First Affiliated Hospital of Shandong First Medical University, Hefei Institute of Physical Science in Chinese Academy of Sciences, Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, and National Engineering Research Center of Cell Products for their technical support. This work was supported by grants from the project Youth Fund supported by Shandong Provincial Natural Science Foundation (ZR2020QC097), Fujian Provincial Ministerial Finance Special Project (2021XH018), Jiangxi Provincial Key New Product Incubation Program Funded by Technical Innovation Guidance Program of Shangrao City (2020G002), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), Medical Innovation Project of Fujian Provincial Health and Health Commission (2019-CX-21), Natural Science Foundation of Jiangxi Province (20212BAB216073), Key project funded by Department of Science and Technology of Shangrao City (2020AB002, 2020 K003, 2021F013), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), Gansu Key Laboratory of Molecular Diagnosis and Precision treatment of surgical tumors (18JR2RA033), and Horizontal Project upon Retrospective Analyses of COVID-19 (2020XH001).

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

Not applicable.

Appendices and nomenclature

h-BN

hexagonal boron nitrides

BP

black phosphorus

TMDCs

palladium

Pd

Low-glucose DMEM with GlutaMax™ supplemented with 15% human serum

TMOs

transition metal oxides

EPR

enhanced permeability and retention

CT

computed tomography

MRI

magnetic resonance imaging

PET

positron emission tomography

PSMA

prostate-specific membrane antigen

HA

hyaluronic acid

TaOx

tantalum oxide

TaCZ

carboxybetaine zwitterionic-coated tantalum oxide

SPIO

superparamagnetic iron oxide

rGO

reduced graphene oxide

MNPs

magnetic nanoparticles

GCE

glassy carbon electrode

TME

tumor environment

TMDC

transition metal dichalcogenides

ROS

reactive oxygen species

PBM

photobiomodulation

(PDT)

photodynamic therapy

GSH

glutathione

PTT

photothermal therapy

irAEs

immune-related adverse events

CDT

chemodynamic therapy

PVP

polyvinylpyrrolidone

MSNs

mesoporous silica nanoparticles

MR

magnetic resonance (MR).