1. Introduction

In the past decades, nanomedicine has been extensively developed for versatile medical applications ranging from diagnostic imaging [1-8] to therapy [9-11]. These nanosystems can improve the therapeutic efficiency by altering their in vivo biodistribution [12] and prolonging the circulation within the body [13, 14]. Especially, researchers have explored abundant stimuliresponsive nanoplatforms for targeted imaging and therapeutic treatments with high disease specificity [15]. These stimuliresponsive nanosystems change their physiochemical or biological performance, and release agents for diagnosis and therapy when exposed to corresponding stimuli [16, 17]. These stimuli include extrinsic triggers (e.g., magnetic field [18, 19], ultrasound [20, 21] and X-ray irradiation [22]) and internal triggers [23-25] (e.g., pH [26-28], reducing condition [28-31], enzyme [32, 33] and H₂O₂ [7]). Among these stimuli-responsive modalities, pH-responsive nanoplatforms have been extensively explored because of the mild acidic microenvironment of tumor [5, 7, 34, 35]. This review focuses on the H₂O₂-sensive nanomedicine which can be endowed with more specific theranostic applications since H₂O₂ is one kind of important reactive oxygen species (ROS) in human body [36].

Free radicals and other ROS [37-44], are present in the human body, which are also persistently generated. There are various kinds of free radicals in physiological environment, such as the superoxide radical (O₂^•-) [39-41], hydroxyl (OH^•) [39-41], and nitric oxide (NO^•) [38-42]. Hydrogen peroxide (H₂O₂) [45, 46], singlet oxygen (¹O₂) [39-41, 47] and peroxynitrite (ONOO^-) [38-42] are not the typical free radicals but they can be easily transformed into free radicals in physiological conditions. ROS is the generic term of free radicals and nonradicals. Under normal circumstances, the generation of ROS and the antioxidant defenses of organism maintain a dynamical balance. However, this balance can be broken when it is triggered by external stimulation (such as injury). The imbalance of ROS and antioxidant defenses will induce oxidative stress which can cause cell damage and death. It has been verified that numerous human diseases are associated with severe oxidative stress [37, 38, 48-51], such as Parkinson's disease [51], neurotoxins [48] atherosclerosis, etc.

Hydrogen peroxide (H₂O₂) [39-41] is generally regarded as the most abundant and stable ROS. On one hand, it can be converted to hydroxyl radical (OH^•), which is more toxic than other ROS with a short half-time of only 10^-9 s. On the other hand, H₂O₂ can be generated in vivo when catalyzed by O₂^•-dismutase. Therefore, H₂O₂ plays a vital function in balancing the free radicals. Based on the close relationship of ROS with some diseases, the ROS detection, especially H₂O₂, is believe to provide important physiological and biological information for diagnosis of these diseases.

To defense against ROS-induced damage in physiological conditions, the enzymes of glutathione peroxidase and catalase play a key role [36]. Both of these two enzymes can remove H₂O₂. Additionally, superoxide dismutase (SOD) [43], which can convert O₂^•-into H₂O₂ and O₂, exert the specific function in weakening inflammation induced by excessive ROS. All of the abovementioned enzymes can be used to regulate the ROS balance (especially H₂O₂) and further relieve the physiological damages. It offers a new strategy for the treatment of H₂O₂-relevant diseases, such as tumor, Alzheimer's disease [51-56] and inflammation [57-60], etc.

Especially, the malignant tumor cells can produce excessive H₂O₂, therefore the tumor microenvironment presents a significantly high H₂O₂ concentration as compared to normal tissues. Catalase, which can catalyze H₂O₂ to generate oxygen, provides a feasible method to modulate the tumor hypoxia [61-64] and improves the efficiency of photodynamic therapy (PDT) [65-67] and chemo/radiotherapy [68, 69]. The tumor hypoxia [70] (the imbalance between the intake oxygen and the consumption of oxygen) is one of the specific features of solid tumors, which is induced by the rapid proliferation of cancer cells and the abnormal angiogenesis [71-77]. Photodynamic therapy (PDT) and radiotherapy (RT) [68], as non-invasive treatments of tumor, have shown the high therapeutic efficiency. However, the therapeutic species as produced by PDT/RT is the different kinds of ROS [78]. Therefore, the therapeutic efficiency of PDT/RT would be significantly lowered due to the inadequate oxygen supply in hypoxic solid tumors. As a result, using catalase or catalase-mimic metallic oxide (e.g., MnO₂ and CeO₂) to catalyze H₂O₂ and generate oxygen can be developed to improve the therapeutic efficiency/outcome of PDT/ RT [68].

Because of relatively high H₂O₂ concentration of some diseases, H₂O₂-responsive nanosystems can be developed for some specific biomedical applications, including diagnostic imaging [79, 80], relieving tumor hypoxia [71], enhanced PDT [79], controllable drug release [81] and therapy of certain diseases [58-60] (Scheme 1). Furthermore, since the oxidation process of glucose into gluconic acid by glucose oxidase (GOx) can generate H₂O₂ as the main byproduct, the detection of glucose concentration of diabetes [44, 82] can be translated into detecting H₂O₂, which provides a new method for the diagnosis and treatment of diabetes by using GOxcoated nanosystems. Based on the specific functions of H₂O₂ for theranostic applications and the fast development of this field, this review will focus on the design and application of H₂O₂-responisive theranostic nanoplatforms for versatile theranostic applications. Following the discussion on several representative paradigms of H₂O₂-responsive nanosystems, the facing challenges and future developments of this research field are also briefly discussed, aiming to further promote the clinical translation of this unique stimuli-responsive theranostic modality.

2. H₂O₂-responsive diagnostic imaging

Nanoparticles-based contrast agents have been extensively explored for various diagnostic-imaging modalities (e.g., MRI, ultrasound imaging, computed tomography, positron emission tomography) because they can significantly improve the imaging precision or monitor the therapeutic process [1-8, 83]. Especially, the imaging modality with specific responses to the diseases can achieve the imaging specificity and efficiency. In this respect, H₂O₂-responsive nanosystems can be used to achieve the specific imaging effect in the lesion regions with high H₂O₂ concentration locally as compared to normal tissues [84-88].

Although various pH-responsive imaging agents have been developed for tumor imaging [89-91], very few reports have been found to focus on the detection of reactive oxygen species (ROS). Wang et al. proposed one kind of hybrid nanogel probe (SGC), which was constituted by superparamagnetic iron oxide (SPIO) particles, two kinds of enzymes (catalase and superoxide dismutase), and glycol chitosan gel [85]. SGC could generate bubbles (oxygen gas) continuously when triggered by 50 μmol/L H₂O₂ (Fig. 1a and b), making it a desirable US contrast agent in physiological microenvironment (Fig. 1c). The generation of oxygen microbubbles included two steps: (ⅰ) superoxide (O₂^⋅) in the tissues was converted into H₂O₂ and O₂ by superoxide dismutase; (ⅱ) the generated H₂O₂ was then converted to water and O₂ by catalase (Fig. 1d). The rapid generation of abundant O₂ induced the formation of bubbles, which then served as USimaging contrast agent. The enhanced US-imaging performance was further verified on VX2-tumor-bearing rabbits on both transverse and longitudinal scanning orientations to demonstrate the high US-imaging performance (Fig. 1e and f). This result demonstrates the possibility of the decomposition of H₂O₂ to generate O₂ bubbles for US imaging.

As H₂O₂ is an important indicator in diagnosis of some diseases such as lung inflammation, cystic fibrosis, etc. Precise non-invasive detection of H₂O₂ is particularly important. Christopher J. Chang et al. have developed a reaction-based MRI contrast agent for detecting H₂O₂ [92]. As shown in Fig. 2a, hyperpolarized ¹³C was used as the MRI contrast agent and the reaction of α-ketoacids oxidized by hydrogen peroxide to carboxylic acids was used as the H₂O₂-detecting mechanism. ¹³C NMR spectra showed that hyperpolarized ¹³C-BFA could be rapidly oxidized to ¹³C-BA in the presence of H₂O₂ (the peak position of ¹³C-BA appeared at 176 ppm, and 13C-BFA as a dualpeaks cantered at 173.5 ppm) (Fig. 2b). From the result of ¹³C NMR spectra, the dependence of the ratio of ¹³C-BA and ¹³C-BFA versus the concentration of H₂O₂ was acquired, indicating the feasibility of using ¹³C-BFA as the H₂O₂-responsive MRI contrast agent (Fig. 2c). In fact, the MRI images verified that ¹³C-BFA presented an enhanced T₂-weighted MR imaging with the increase of H₂O₂ concentration (Fig. 2d-h).

3. Attenuating tumor hypoxia

Hypoxia [61, 62, 70-77] is a general feature of various burgeoning solid tumors, which is usually caused by the proliferation of tumor cells but the intake oxygen can't balance the oxygen consumption [63, 64]. Unfortunately, hypoxia plays a significant role in tumor proliferation and resistance to radio-/chemo-and photodynamic therapy [93]. As a result, attenuating tumor hypoxia is a feasible strategy to improve the efficacy of tumor treatments. A variety of methods have been developed to relief tumor hypoxia, including reducing the consumption of oxygen [94], increasing intratumoral blood flow [95] and using oxygen reservoirs for more intake oxygen [68, 96], Especially, the decomposition of the intratumoral hydrogen peroxide (H₂O₂) to generate oxygen has been utilized to alleviate hypoxia [88, 97].

Based on the high catalase-like performance of MnO₂ for the decomposition of H₂O₂, MnO₂ nanoparticles (NPs) have been used to catalyze H₂O₂ decomposition and generate O₂ for relieving the tumor hypoxia. Moreover, hyaluronic acid (HA) was adopted for reprogramming M2-skewed tumor-associated macrophages (TAMs) of pro-tumor to anti-tumor M1 macrophages. Therefore, HA-MnO₂ NPs had the ability to relief tumor hypoxia and enhance chemotherapy efficiency simultaneously. Furthermore, mannan was modified on the surface of HA-MnO₂ NPs to target the tumor [98]. As a result, Man-HA-MnO₂ NPs can alleviate tumor hypoxia and change the M2-TAMs into M1 macrophages, which could modulate the tumor chemo-resistance (Fig. 3a). From the immunofluorescence images of tumor sections, the increase of M1 macrophages and the decrease of M2-TAMs in tumors were observed (Fig. 3b). Especially, the influence of Man-HA-MnO₂ NPs on tumor oxygen levels can be obviously observed by using blood oxygen level-dependent MRI (BOLD MRI) (Fig. 3c). With the increase of observing duration, the T₂^* values of tumor treated with Man-HA-MnO₂ NPs increased significantly. This paradigm provides the direct evidence that the decomposition of H₂O₂ could improve the tumor oxygen level and enhance the chemotherapeutic efficiency subsequently.

An intelligent albumin-MnO₂ NPs were proposed as H₂O₂-responsive nanocarriers for modulating tumor hypoxia [99]. Human serum albumin (HAS) went through a biomineralization process with the addition of manganese ions in NaOH solutions and finally turned into HAS-MnO₂-Ce6&Pt (HMCP) NPs. These HMCP NPs could catalyze the decomposition of H₂O₂ to generate oxygen and modulate the hypoxia of tumor tissue (Fig. 4a). This assumption has been verified from the immunofluorescence images of tumor sections. The hypoxia areas decreased obviously when the 4T1 tumor-bearing mice were treated with HMCP NPs as compared to the control group without the treatment (Fig. 4b).

For attenuating tumor hypoxia and improving the efficiency of radiotherapy, a novel type of catalase-encapsulated TaOx nanoshells (TaOx@Cat) were explored [69]. Furthermore, to improve the biocompatibility, PEG-modified TaOx@Cat (PEG-TaOx@Catalase) were further synthesized (Fig. 5a). The as-synthesized TaOx@Cat nanoshells exhibited high mono-dispersity with uniform sizes (Fig. 5b). Moreover, the encapsulation of catalase could generate oxygen sequentially in H₂O₂ solutions (Fig. 5c and d). The in vivo experiments further verified the capability of PEG-TaOx@Catalase to alleviate tumor hypoxia (Fig. 5e-g) and enhance the radiotherapy efficiency subsequently.

4. Enhancing photodynamic therapy

Photodynamic therapy (PDT) [65-67], as a non-invasive therapeutic modality, has attracted extensive attention and been approved by United States Food and Drug Administration (FDA). However, the generation of ROS, which plays a key role in PDT treatment, highly depends on the oxygen level in tumor tissues. Therefore, tumor hypoxia is deemed to weaken the therapeutic efficiency of PDT. Fortunately, H₂O₂ overexpressed in tumor can be utilized to generate oxygen for mitigating hypoxia, so it is also anticipated to have the capability for improving the PDT efficiency [86]. On this ground, several kinds of H₂O₂-triggered nanoplatforms have been developed for enhancing PDT efficiency [78, 79, 100-103].

As aforementioned, MnO₂ can react with H₂O₂ to generate oxygen. Since oxygen is a necessarily required in the PDT process, MnO₂ is also expected to play a significant role in enhancing the PDT efficiency [104]. As a typical paradigm, MnO₂ and Ce6 (a typical photosensitizer) were co-coated in poly(allylamine hydrochloride) (PAH) and then packaged in the polymer polyacrylic acid (PAA) shell [104]. To further improve the stability of NPs in physiological condition, PEG was anchored onto the surface of the pre-formed NPs to form Ce6@MnO₂-PEG composite nanosystems (Fig. 6a). These Ce6@MnO₂-PEG NPs significantly alleviated the tumor hypoxia (Fig. 6b), endowing the cancer cells with high sensitivity to PDT treatment. Importantly, the substantially suppressed tumor growth (Fig. 6c) and the H&E staining results (Fig. 6d) of the tumor-bearing mice treated after the treatment with Ce6@MnO₂-PEG and laser further verified the high therapeutic efficiency of Ce6@MnO₂-PEG for hypoxia tumor.

In addition to inorganic MnO₂ NPs, the organic enzyme catalase could also be utilized to catalyze the decomposition of hydrogen peroxide and generate oxygen afterwards. For instance, the H₂O₂-activatable HAOP NPs were elaborately constructed with the loaded catalase, black hole quencher-3 (BHQ-3), methylene blue (MB) and c(RGDfk) modified poly(D, L-lactic-co-glycolic acid) (PLGA) shell [105]. Each component of this nanosystem has it's unique function: (ⅰ) catalase was loaded in PLGA shell and used to catalyze the decomposition of H₂O₂ and generate O₂; (ⅱ) BHQ-3 was applied to quench the excited photosensitizer; (ⅲ) MB as a typical photosensitizer was loaded for tumor PDT; (ⅳ) c(RGDfk) as a classical tumor-targeting ligand was anchored for targeted DPT; (ⅴ) PLGA shell served as nanocarriers for catalase, MB and BHQ-3 (Fig. 7a). In the presence of H₂O₂, the catalase component of HAOP NPs catalyzed H₂O₂ to generate O₂, making the tumor cells sensitive to PDT treatment. In addition, the generation of oxygen also caused the PLGA shell collapse and controllable release of MB (Fig. 7b). Furthermore, the effect of H₂O₂-activatable HAOP NPs on improving phototoxicity of tumor cells was evaluated by confocal fluorescence assay (Fig. 7c) and the results verified the capability of HAOP NPs for enhanced PDT treatment.

Based on the high reactivity of MnO₂ with H₂O₂, an O₂-generating hybrid nanoparticle (IHM, ICG-HANP/MnO₂) with three-modality imaging capability were designed for enhanced PDT of tumor [106]. As shown in Fig. 8a, MnO₂ NPs were encapsulated into hyaluronic acid nanoparticle (HANP), which could react with H₂O₂. During this reaction, the generated O₂ could suppress the tumor hypoxia so that PDT efficiency could be improved. Furthermore, ICG were modified on the surface of HANP which acted as contrast agent for the fluorescent/PA imaging. Compared with free-ICG, IHM presented a tumor-targeting behaviour, causing significantly enhanced diagnostic-imaging contrast (Fig. 8c and d). The results of DLS and TEM (Fig. 8b) verified that MnO₂ NPs and ICG were loaded into IHM simultaneously with nanoscale size and monodispersity. Interestingly, O₂ bubbles generated from the reaction of MnO₂ and H₂O₂ induced a high US imaging signal (Fig. 8e). Therefore, the fluorescent, PA and ultrasound imaging could be simultaneously achieved to monitor the PDT process in real time. Importantly, the tumors of tumorbearing mice treated with IHM were almost completely eliminated, suggesting that O₂-generating IHM could bring with the high PDT efficiency (Fig. 8f and g).

5. H₂O₂-responsive drug-release

As discussed above, the designed H₂O₂-activatable HAOP NPs behaved a sequential and responsive release of MB in presence of H₂O₂. [105] Therefore, similar to mostly explored pH-responsive drug-releasing pattern, H₂O₂-responsive release of loaded agent could also be achieved within the specific microenvironment with overexpressed H₂O₂ amount [81].

Because of the diversity of organic polymers, a variety of bioresponsive degradable polymer capsules have been explored for biomedical applications [17, 102]. On the basis of H₂O₂-degradable polymer matrix, T₁-weighted MRI contrast agent Gd₂O₃ NPs were encapsulated and protected from the aqueous environment [87]. As a result, Gd₂O₃ NPs behaved selective imaging in targeting tissue with higher H₂O₂ concentration as compared to normal tissues (Fig. 9a). As a matter of fact, D1/T₁ values of Gd₂O₃ encapsulated in H₂O₂-responsive polymer NPs exhibited an obvious increase with the elevation of H₂O₂ concentrations (Fig. 9b). TEM images of the morphology of the composite NPs after the incubation with/without 100 μmol/L H₂O₂ at varied durations were observed. It has been found that these NPs behaved a H₂O₂-responsive degradation which would further facilitate the release and MR imaging of Gd₂O₃ contrast agents (Fig. 9c).

6. Diagnosis and treatment of inflammation

It has been demonstrated that excessive H₂O₂ generation is one of the specific features of inflammation tissues [58-60]. Therefore, the detection of H₂O₂ might be effective in inflammation diagnosis. In addition, H₂O₂ molecules could be potentially converted to hydroxyl radical, which might induce severe tissue damage and apoptosis. Therefore, the consumption of H₂O₂ for some H₂O₂-relevant diseases is expected to achieve the enhanced efficiency [107].

Hepatic ischemia/reperfusion (I/R) injury is the most common problem in a variety of liver clinical surgeries, which further caused tissues damages and inflammatory diseases [108]. Especially, I/R injury could also cause the generation of abundant ROS (hydroxyl radical, H₂O₂, etc.). Therefore, the consumption of H₂O₂ and triggering the release of antiphlogistic are considered as a feasible method to relieve hepatic I/R injury. On this ground, H₂O₂-responsive bubble-generating PVO microparticles were designed to conquer hepatic I/R injury (Fig. 10a) [108]. The PVO microparticles could decompose responsive to H₂O₂, which further released vanillin (as antioxidant and anti-inflammatory drug) and generated CO₂ bubbles to serve as contrast agents of ultrasound imaging. The ability of generating CO₂ bubbles of PVO microparticles were directly observed by TEM. The images also showed the collapse of the PVO microparticles to release vanillin simultaneously (Fig. 10b). H&E staining images of liver tissues revealed that PVO microparticles tremendously attenuated the tissue damage induced by hepatic I/R injury.

7. Diagnosis and treatment for diabetic

It has been well demonstrated that glucose can be oxidized by glucose oxidase (GOx) to generate H₂O₂ simultaneously, which provide possibility and foundation for the detection of H₂O₂ to monitor and regulate the glucose concentration [82, 109, 110].

The painless and real-time glucose-monitoring therapy of diabetic remains a great challenge. Recently, a painless microneedle-array patch was developed for achieve this goal [110]. In this work, researchers developed hypoxia and H₂O₂ dualsensitive diblock copolymer self-assembly vesicles (d-GRPs), and then used d-GRPs loaded with insulin and GOx [110]. These dual-sensitive vesicles could disassemble to release insulin as triggered by higher glucose concentration (Fig. 11a). GOx oxidized glucose to generate H₂O₂ and consume the oxygen. Simultaneously, hypoxia and H₂O₂ dual-sensitive diblock copolymer could consume H₂O₂ to avoid possible inflammation (Fig. 11b). TEM test verified the vesicles disassembly after the incubation with glucose (Fig. 11c). Furthermore, the in vivo experiments on mouse verified that the d-GRP(E)-loaded microneedles wouldn't induce the significant damage. This work provides a feasible method to potentially improve the quality of diabetic patients' life.

In addition to MnO₂ NPs, other inorganic metallic oxides can also react with H₂O₂ for biomedical applications. CeO₂ NPs are one of the mostly explored nanosystems for versatile biomedical purposes, including the reaction with H₂O₂. [109] For instance, CeO₂ NPs with uniform spherical shape were synthesized via a simple hydrothermal method (Fig. 12a). In vitro experiment proved its anti-oxidation performance when the cells were incubated with CeO₂ NPs and 75 μmol/L H₂O₂ (Fig. 12b). Raman spectra were used to explore the mechanism of the reaction of CeO₂ NPs with H₂O₂ (Fig. 12c). It was proved that with the addition of H₂O₂, Ce⁴⁺ was reduced into Ce³⁺ and H₂O₂ was oxidized to generate O_2⋅. Furthermore, in the mild acidic microenvironment, the H₂O₂ could further oxidize Ce³⁺ into Ce⁴⁺, which guaranteed the continuous anti-oxidation process of ceria NPs.

8. Conclusions and outlook

The rapid development of nanotechnology and materials chemistry has spurred the fast progress of theranostic nanomedicine very recently. Over the past decades, various nanosystems with specific functionalities for efficient diagnosis and therapy of diseases have been explored to satisfy the strict clinicalapplication requirements. Since stimuli-sensitive nanomedicine can induce site-/time-specific theranostic performance, the microenvironment-triggered theranostic nanoplatform have aroused the great attention of scientific community recently. On this ground, H₂O₂-responsive nanoplatforms have been extensively explored to exert the specific theranostic performance in biomedical applications because of the high level of overexpressed H₂O₂ as a hallmark of some diseases, such as malignant tumor, inflammation, neurodegenerative diseases (Alzheimer and Parkinson), etc. The very-recent specific biomedical applications of H₂O₂-responsive nanoplatforms, including diagnostic imaging, attenuating tumor hypoxia, enhancing the therapeutic efficiency of photodynamic therapy/radiation therapy/chemotherapy and theranostic of inflammation/diabetic, have been summarized and discussed in this review.

In addition to aforementioned biomedical applications of H₂O₂-responsive theranostic nanomedicine, there are also other application paradigms, such as neurodegenerative diseases (Alzheimer [53-56], Parkinson [51], etc.). However, the development of H₂O₂-responsive nanomedicine is much slower as compared to other stimuli-responsive modalities, such as pH responsibility. There are still some unresolved critical issues those restrict their extensive biomedical applications and clinical translations.

First, the fabrication of H₂O₂-responsive nanosystems is still challenging. Very few organic (e.g., enzyme-loaded organic NPs) or inorganic (e.g., MnO₂, CeO₂, Fe₃O₄) nanoplatforms have been successfully developed for this specific responsibility. The fast development of nano-synthetic chemistry makes the exploring of new theranostic nanoplatforms with H₂O₂ responsibility possible. Especially, the following researches should focus on the large-scale fabrication of these nanosystems to guarantee their further potential industrial translation.

Second, H₂O₂-responsive theranostic modalities are still very rare. The tumor tissues overexpresses H₂O₂, but the H₂O₂ level is still low, which cannot guarantee the following theranostic process with high efficiency. Therefore, the theranostic efficiency of these developed nanoplatforms should be further enhanced. In addition, other H₂O₂-responsive theranostic modalities should be further developed to take the specific advantage of this responsive modality for theranostic applications. For instance, the Fe₃O₄-based Fenton reaction has been designed for chemo-dynamic therapy against tumor [111].

Third, the biosafety of these H₂O₂-responsive nanoplatforms should be fully revealed to further guarantee their clinical translation. The current researches mainly focus on the exploring of new H₂O₂-responsive nanoplatforms and improving their theranostic performances, ignoring their biological effect and biosafety. Therefore, the following researches should focus on their systematic in vivo biosafety evaluations of these H₂O₂-responsive nanoplatforms for guaranteeing their further clinical translation.

Last but not least, more extensive collaborations should be established based on the multidisciplinary nature of this research field. The progress of H₂O₂-responsive theranostic nanomedicine should be devoted by the researcher with varied research background, including material science, chemistry, biology and biomedicine. The close collaborations among different researches provide the bases for the potential clinical translation of this theranostic modality.

As a new but highly versatile emerging responsive theranostic modality, H₂O₂-responsive theranostic nanomedicine has shown its high specificity and theranostic performance for various biomedical applications, which has paves a new way for the theranostic of diseases with overexpressed H₂O₂. As far as the aforementioned critical issues are adequately solved, this unique H₂O₂-responsive theranostic nanomedicine is highly expected to enter the clinical stage to benefit the personalized biomedicine in the near future.

Acknowledgments

We greatly acknowledge the financial support from the National Key Research and Development Program of China (No. 2016YFA0203700), National Natural Science Foundation of China (No. 51672303), Shanghai Excellent Academic Leaders Program (No. 14XD1403800), Young Elite Scientist Sponsorship Program by CAST (No. 2015QNRC001), Youth Innovation Promotion Association of the Chinese Academy of Sciences (No. 2013169) and Development Fund for Shanghai Talents (2015).