Recent development of pH‐responsive theranostic nanoplatforms for magnetic resonance imaging‐guided cancer therapy

Abstract The acidic characteristic of the tumor site is one of the most well‐known features and provides a series of opportunities for cancer‐specific theranostic strategies. In this regard, pH‐responsive theranostic nanoplatforms that integrate diagnostic and therapeutic capabilities are highly developed. The fluidity of the tumor microenvironment (TME), with its temporal and spatial heterogeneities, makes noninvasive molecular magnetic resonance imaging (MRI) technology very desirable for imaging TME constituents and developing MRI‐guided theranostic nanoplatforms for tumor‐specific treatments. Therefore, various MRI‐based theranostic strategies which employ assorted therapeutic modes have been drawn up for more efficient cancer therapy through the raised local concentration of therapeutic agents in pathological tissues. In this review, we summarize the pH‐responsive mechanisms of organic components (including polymers, biological molecules, and organosilicas) as well as inorganic components (including metal coordination compounds, metal oxides, and metal salts) of theranostic nanoplatforms. Furthermore, we review the designs and applications of pH‐responsive theranostic nanoplatforms for the diagnosis and treatment of cancer. In addition, the challenges and prospects in developing theranostic nanoplatforms with pH‐responsiveness for cancer diagnosis and therapy are discussed.


INTRODUCTION
Nowadays, cancer is one of the most severe illnesses menacing physical health of citizens. [1] To fight against cancer, a wide range of treatment methods utilizing the characteristics of tumor microenvironment (TME) have been developed. [2][3][4] TME plays a significant part in the initiation and progression of tumors, [5] which is also constantly evolving as a consequence of tissue remodeling, metabolic disturbances in the tumor, and alterations in the recruitment of stromal cells. [6] On account of the rapid progress of tumor cells and their high demands for metabolism, the TME entails changes and variations in the biochemical conditions within the tissue, such as hypoxia, resulting in the up-regulated glycolytic

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In the field of nanomedicine, attention has recently been drawn to the development of theranostic nanoplatforms with both diagnostic and therapeutic abilities, as it provides excellent chances to combat a variety of major diseases. [12][13][14] On this account, theranostic nanoplatforms sensitive to the slightly acidic environment are quite advantageous for the detection, imaging as well as therapy of tumors. Owing to passive and active tumor targeting as well as the pH-sensitivity, theranostic nanoplatforms are competent to deliver therapeutic agents and diagnostic agents specifically to the targeted tumor tissue for concurrent surveillance of pathological process and biological responses to the treatment. [15] The main objective of any type of cancer therapy (chemotherapy, radiotherapy, photodynamic therapy (PDT), gene therapy, immunotherapy, hyperthermia, etc.) is to convey the required therapeutic agents specifically to the malignant tumor sites and minimize the side effects to normal tissues. In this respect, the biocompatible and biodegradable nanoplatform, in which cargo release is commonly controlled by pH values and/or other stimuli, is imperative to convey the therapeutic agents specifically to tumor sites, while diminishing any undesirable side effects. [16] As one of the most essential components of the theranostic nanoplatform, imaging probes are capable of improving the specificity of the contrast enhancement and providing elaborate characteristics of tumor for clinical diagnosis. [12,[17][18][19][20] By virtue of the non-invasive property, magnetic resonance imaging (MRI) technique with non-limited penetration depth and high spatial resolution is quite competent to provide in vivo tomographic details of pathological tissues in real time. [17,21] Consequently, MRI contrast agents (CAs) have turned into one of the most notable diagnostic competitors in fabricating theranostic nanoplatforms. [15,22] The selective delivery of CAs such as superparamagnetic iron oxide nanoparticles, Mn(II) complexes, and Gd(III) complexes by tailor-made nanoplatforms, including block copolymers, [23][24][25][26] liposomes, [27] graphene oxide, [28,29] hydrogels, [30] to the targeted tumor site is critical in endowing the theranostic nanosystem with ultrasensitive MRI contrast ability.
This review summarizes the recent progress in pHresponsive theranostic nanoplatforms that integrate MRI-based diagnostics and a variety of therapeutic modes for tumor detection, imaging, and therapy. First, we outline the design of pH-responsive nanoplatforms, which consists of organics-based and inorganics-based pH-responsive nanoplatforms. Second, MRI contrast agents applied in pHresponsive theranostic nanoplatforms are summarized, such as T 1 -weighted (T 1 ) MRI CAs, T 2 -weighted (T 2 ) MRI CAs, and T 1 -T 2 dual modal MRI CAs. Furthermore, a variety of MRI-guided therapeutic modes, including MRI-guided single therapeutic mode and MRI-guided combined therapeutic modes, produced by pH-responsive theranostic nanoplatforms are discussed. The final section describes the challenges and prospects in developing theranostic nanoplatforms with pH-responsiveness for cancer diagnosis and therapy.
For instance, the pH-responsive polymeric micelles (CR-CAs) made from amphiphilic block copolymers were self-assembled, which consist of poly(ethylene glycol)-bpoly(l-histidine) (PEG-p(l-His)) and PEG-b-poly(l-lactic acid)-diethylenetriaminopentaacetic acid dianhydridegadolinium chelate. And they would be destabilized as a result of the protonation of amino groups in p(l-His) blocks under acidic conditions of tumor, leading to their break apart into protonated water-soluble polymers ( Figure 1A). [23] In addition, many other block copolymers containing pH-responsive tertiary amino groups have also been applied to encapsulate hydrophobic contrast agents or drugs for possible acidtargeting delivery. [24,31] For example, Chen et al. employed poly(ethylene glycol)-poly(2-(hexamethyleneimino)ethyl methacrylate) to encapsulate gadolinium metallofullerenepolypyrrole nanoparticle (denoted as PEG-GMF-PPy NP) for pH-activatable and tumor-specific imaging. [31] Besides, poly(β-amino ester)s were reported to present weakly basic character due to their tertiary amine groups, which leads to being water-soluble at a lower pH and insoluble in water at a neutral pH. [32] Thus, some researchers have fabricated a great deal of pH-responsive polymeric micelles by introducing poly(β-amino ester) block to form pH-responsive probes. [33,34] pH-sensitive hydrogels comprising ionizable functional groups can respond to alterations in the surrounding environment and unload cargo through pH-responsive release mechanisms. [35] Yang and co-workers fabricated a PEG-based hydrogel containing imidazole functional groups to endow the nanoplatform with pH-responsiveness to tumor acidity. Therefore, the amine functional groups in imidazole moieties are mainly protonated in an acidic environment of tumor, leading to an enhanced water absorption into the hydrogels and rapid release of loaded cargo. [30] Lin and co-workers constructed poly(acrylic acid) (PAA) modified lanthanidedoped GdVO 4 nanoparticles by filling PAA hydrogel into GdVO 4 hollow spheres, which exhibited drug-loading and pH-dependent drug releasing characteristics. [36] As part of the polymer family, poly(acrylic acid) (PAA) which is biodegradable has been considered as a charming candidate for drug delivery as a result of its diminished toxicity, antigenicity, and immunogenicity. [37,38] Moreover, the large number of carboxyl functional groups of PAA not only makes the nanoparticles hydrophilic, but can efficiently load some drugs such as doxorubicin (DOX), [39] cisplatin, [40] through electrostatic interaction, which mainly exists between the charged active functional groups. And the release of drugs from PAA would be triggered in an acidic environment due to the destruction of electrostatic interaction. In addition, polyethylenimine with an abundance of amino groups was coated onto hydroxylated mesoporous nanosilica via electrostatic interactions as well as hydrogen bonds and served as pH-sensitive gatekeepers for the control of drug release since both electrostatic interactions and hydrogen bonds are sensitive to protons. [41] In addition, some other kinds of polymers were employed to conjugate with anticancer drugs through pH-responsive hydrazone bonds, which could be quickly cleaved to realize controlled drug release in acidic tumor sites. For example, anticancer drug doxorubicin could simply conjugate with hydrazine-functionalized poly(ethylene glycol) (SH-PEG) via pH-sensitive hydrazone bonds. [42] Sun et al. linked such conjugation (SH-PEG-DOX) onto gold nanocrystals to construct pH-responsive nanoplatform (denoted as UCNPs@Au-DOX). And the pH-responsive hydrazone linkages would be quickly cleaved to achieve targeted drug release in the acidic environment of tumor. [43] Similarly, some other researchers have applied hydrazine modified salep, [44] hydrazide tailored poly (methyl methacrylate), [45] acylhydrazine modified poly (amidoamine) dendrimers [46] and block copolymer [47] to conjugate with DOX via pH-responsive hydrazone bonds for targeted drug release.

. Biological molecule-based pH-responsive nanoplatforms
Chitosan is a natural biodegradable and biocompatible polysaccharide based on chitin and has been widely employed for multiple biomedical applications, namely drug delivery, tissue engineering, and wound healing. [48,49] Recently, chitosan has been reported to possess excellent drug loading property as well as improved pH-sensitive drug release ability. [48] In this case, many researchers have reported the synthesis of chitosan-functionalized nanoplatforms for drug/contrast agents loading and pH-responsive release. [50][51][52][53] In addition, another kind of polysaccharide, carboxymethyl dextran (CMD), which exhibits good biocompatibility and biodegradability, could be used as non-toxic ingredients in formulations and reagents for binding other components. For example, Zhang et al. chemically modified CMD on the surface of porous manganese phosphate nanoparticles via pH-sensitive boronate esters (denoted as PMP-CMD NP), which would be cleaved under acidic conditions of tumor, leading to the dissociation of CMD from the surface. [54] pH low insertion peptide (pHLIP) is comprised of 36 amino acids and has exhibited effectiveness and selectivity to target the acidic TME. By means of the protonation of aspartic acid residues in an acidic environment, pHLIP can achieve a conformational transition to develop the α-helix insertion mode, which is unidirectionally inserted into the membrane with C-terminal inside. [55,56] Consequently, many researchers have applied pHLIP as the pH-responsive ligands to enhance the accumulation of magnetic nanoparticles within tumor sites, which showed great biomedical potential to target acidic TME for tumor detection and diagnosis through MRI ( Figure 1B). [57][58][59] Except for pHLIP, some other peptides are also sensitive to acidic TME, generating targeting activity. For instance, Kim and co-workers reported on a lower pH-triggered drugeluting nanocomposite (denoted as pH-DEN) consisting of pH-sensitive synthetic peptides with lipid tails as the gatekeeper. In an acidic environment, the synthetic peptides were destabilized due to ionization of imidazole functional groups and transformed into a charged water-soluble form, thus triggering the controllable drug release from nanoparticles. [60] Lee et al. conjugated 2,3-dimethylmaleic acid (DMA) with poly(l-lysine) via the dehydration condensation of carboxyl groups with amino groups and realized surface charge switching for the improvement of tumor recognition efficiency with the dissociation of DMA under acidic TME. [61] Moreover, Zheng and co-workers designed one kind of cell penetrating peptides (CPPs), H 7 K(R 2 ) 2 , which can react to the slightly acidic environment of the tumor site. More specifically, this pH-sensitive peptide would generate CPP characteristics under acidic conditions of tumor and non-CPP characteristics in a neutral environment of healthy tissues. [62] Liposomes have drawn much attention as pH-responsive platforms owing to their size control properties, biocompatibility, and drug-loading capacity. [63] For instance, nanohybrid liposomes covered by amphiphilic hyaluronic acid-ceramide were developed to specifically deliver anticancer drugs into tumor sites. Drug release from the fabricated nanohybrid liposome could be enhanced at lower pH versus physiological pH. [27] Nguyen and co-workers reported on the liposomebased polymer-caged nanobins acting as a nanoscale delivery system, which allowed for a high dose encapsulation of anticancer drugs through an ion-gradient-mediated drugloading approach. And the nanoplatform exhibited pHdependent drug releasing behavior in the acidic environment of tumor. [64] .

Organosilica-based pH-responsive nanoplatforms
Although silica exhibits no pH-responsive property, the organosilica nanoparticles modified with a range of organics could conjugate with other components through pHresponsive chemical bonds, which would be cleaved under acidic conditions. Among them, boronate ester bond can be formed via the condensation of polyalcohol and boronic acid for the connection of silica nanoparticles with other components. For example, Chou et al. tethered polyalcohol saccharide-derivative silane on the outside of mesoporous silica nanoparticles to connect with boronic acid modified gold nanoparticles through boronate ester bonds, which can be hydrolyzed under acidic conditions of the tumor and realize pH-controlled release ( Figure 1C). [65] Another kind of pH-responsive chemical bond for the connection of organosilica nanoparticles with other components is imine bond, which can be formed by reacting aldehydes or ketones with amine derivatives. By making use of imine bonds, Zheng and co-workers sealed hollow mesoporous organosilica nanoparticles with the enzyme catalyst glucose oxidase (GOD). And the blocking GOD gatekeeper could be eliminated through pH-induced hydrolyzation of imine bonds. [66] Additionally, acetals are formed through the condensation of aldehydes and alcohols and can be hydrolyzed in an acidic environment. Based on this characteristic, Lu and co-workers constructed a system (denoted as MEMSN) by modifying acetals on the outside of mesoporous silica, and then conjugating with ultrasmall lanthanide-doped upconverting nanoparticles as the gate keepers. On account of the hydrolyzation reactions of acetals, the loaded anticancer drug DOX achieved pH-responsive burst release under acidic conditions of tumor. [67] .

Metal coordination compound nanoparticles-based pH-responsive nanoplatforms
The coordination compounds have been regarded as a promising candidate to construct theranostic nanoplatforms as a result of the appealing advantages such as the comparatively stable structure, componential tunability, good biodegradability as well as facile surface modification. [68][69][70] Moreover, for some of coordination compounds, the coordinated bonds between metal ions and organic ligands are pH-sensitive and can be broken up under acidic conditions of the tumor, thus resulting in the disintegration of coordination complexes.
Plentiful phenolic hydroxyl functional groups of gallic acid (GA) could strongly coordinate with Fe 3+ to construct a Fe-GA network structure, which is quite stable and barely releases ferric ions in the TME. [71] To deal with this problem, Gao et al. tuned the stability of the Fe-GA coordination compound through the adjustment of GA ligand number in which ferric ion is concurrently coordinated with GA and HO − /H 2 O (denoted as UCNP@GA-Fe). The introduction of such coordinated structure leads to the easier release of ferric ions in the slightly acidic environment (Figure 2A). [71] Recently, nanoscale metal-organic-frameworks (MOFs) have exhibited great potential as promising nanoplatforms for the delivery of therapeutic agents and imaging agents. [72] For instance, the MIL family which is fabricated from nontoxic and biodegradable porous ferric ion carboxylate materials with different compositions and structures has demonstrated large capacity for drug loading and pH-responsive release. [73][74][75] Therefore, some researchers employed MIL-100 which could decompose in an acidic environment to construct pH-responsive cargo release system. [76,77] For example, Chen et al. developed the core-shell MOFs (denoted as CS-MOFs) and the MIL-100 outer shell could achieve pH-dependent delivery of Artesunate. [77] Additionally, some other ferric ion-based coordination complexes such as catechol-Fe 3+ coordinated micelles, [78] Fe-polydopamine (PDA) coordinated nanoparticles, [79] FeOOH clusters, [80] are similarly employed to endow the nanoplatform with pH-responsive characteristic.
As a 2D nanomaterial, layered double hydroxides (LDHs) possess the positively charged host layers similar to brucite structures consisting of edge-sharing octahedral units, in which every metal ion is simultaneously coordinated with six hydroxyl groups. [81] The protonation of hydroxyl groups surrounding metal cations makes LDHs sensitive to weakly acidic environments. Besides, LDHs could be easily doped with diverse metal cations such as Mn 2+ in the brucite-like layers. [82] Inspired by these advantages, researchers developed Mn-based LDHs nanomaterials as enhanced MRI contrast agents with sensitive pH response. [83,84] In addition, Zhu et al. reported on the methotrexate-Mn 2+ (MTX-Mn) based nanoscale coordination polymers (denoted as MTX-Mn@PEG), which were proved to be pH-sensitive and could be decomposed into methotrexate and Mn 2+ in the intracellular acidic environment of tumor. [85] As a member of MOFs family, Zeolitic imidazolate framework-8 (ZIF-8) is composed of Zn 2+ cations and 2methyl imidazolate linkers. The coordination interactions between Zn 2+ ions and imidazolate ions can be affected under acidic conditions because of the effects of protonation, which causes the degradation of ZIF-8. [86] Therefore, it has shown advantageous characteristics of pH-responsiveness in the slightly acidic TME while staying stable in normal physiological environments and has been employed as the drug storage and delivery vehicle for tumor-targeted drug release. [87,88]

. Metal oxide nanoparticles-based pH-responsive nanoplatforms
Manganese oxide nanomaterials developed in recent years exhibit controllable physical and chemical properties, negligible toxicity, and good T 1 contrast effects. [89] As a TMEresponsive biodegradable agent, manganese oxide nanomaterials have aroused considerable interest in tumor-targeted theranostics. [90,91] Some recent researches revealed that manganese oxide materials have TME-sensitive and TMEmodulating features, which could be dissolved into Mn 2+ ions under acidic conditions of the TME. [92] For example, Huang et al. coated MnO 2 onto gold nanorods to construct pHresponsive theranostic nanoplatform. [93] In addition, ultrasmall MnO 2 nanoparticles were also employed as gate keepers to seal mesoporous silica NPs (denoted as USMO@MSN) for pH-responsive cargo release. [94] Moreover, some other researchers have applied manganese oxide nanomaterials such as manganese oxide nanoparticles, [95] honeycomb manganese oxide nanospheres, [96] Two-Dimensional MnO 2 Nanosheets [91] to construct pH-responsive degradable nanocarriers.
Apart from manganese oxide, some other metallic oxide nanomaterials were also reported to be pH-sensitive and were employed to endow the nanoplatform with pH-responsive property. For instance, by making use of gadolinium oxide nanomaterials, Du et al. synthesized pH-responsive Gd 2 O 3 nanoscrolls, which could biodegrade upon encountering the TME and realize targeted delivery of loaded drugs ( Figure 2B). [97] Wang et al. employed the hollow Gd 2 O 3 nanospheres to efficiently load tumor antigens for pHdependent release. [98] In addition, Hou et al. reported on the pH-sensitive Fe 5 C 2 @Fe 3 O 4 nanoparticles in which Fe 3 O 4 shell can discharge ferrous ions effectively for the catalysis of the Fenton reaction and T 1 MRI in acidic environments. [99] Zhang et al. applied ZnO as the gatekeepers to effectively encapsulate the drugs in the mesopores of mesoporous silica NPs till it is disintegrated under acidic conditions of the tumor to achieve on-demand drug release. [12] . Metal salt nanoparticles-based pH-responsive nanoplatforms Calcium carbonate (CaCO 3 ) and manganese carbonate (MnCO 3 ) offer attractive characteristics such as being highly sensitive to acidic environments on account of their intrinsic nature of comprising Ca 2+ /Mn 2+ and CO 3 2− . Therefore, some researchers took advantage of the pH-sensitivity of calcium carbonate to construct pH-responsive theranostic nanoplatform. [100][101][102] Meanwhile, other researchers employed manganese carbonate to endow the nanomaterials with pH-activatable property within the tumor site. [103,104] By virtue of their promise in offering pH-responsive diagnostic functions and therapeutic benefits concurrently, biodegradable and biocompatible metal phosphate nanomaterials have been demonstrated to possess huge potential in tumor theranostic applications. [54] Thus, Zhang et al. developed tumor acidity-activatable nanoplatform based on manganese phosphate with ultrasensitive pH-responsive degradability for the improvement of PDT as well as MRI. [54] Benefiting from their inherently excellent properties such as adequate biodegradation, excellent biocompatibility, and pHcontrolled cargo release, calcium phosphate (CaP) nanoparticles have drawn booming research attention as one of the most advantageous nanomaterials. [105] Consequently, Kataoka and co-workers took advantage of pH-sensitive CaP nanoparticles to confine Mn 2+ ions, which would stay stable (less than 8% Mn 2+ ions were released) at pH 7.4 but would disintegrate and release Mn 2+ ions more rapidly (36% at pH 6.7, 71% at pH 6.5 and over 95% at pH 5) within 4 h ( Figure 2C). [106] Similarly, Huang et al. mineralized glucose oxidase with manganese-doped CaP to construct pH-responsive theranostic nanoplatform for diagnosis and cascade reaction-enhanced cooperative cancer therapy. [107][108][109][110] Other researchers also applied CaP to construct pH-responsive theranostic nanoplatforms, such as loading photosensitizer and prodrug for amplified combination therapy, [111] or encapsulating drug and contrast agents for MRI-guided chemotherapy. [112] Recently, manganese silicate NPs have attracted great interest because of their efficacy of T 1 MRI contrast under slightly acidic and elevated glutathione conditions of the TME, which have been extensively reported as pH-responsive T 1 MRI contrast agents. [113][114][115][116] Moreover, manganese silicate-based theranostic nanoplatforms were designed for MRI-guided pH-responsive delivery of drugs. [117,118] Arsenite (AsO 3 3− ) can coprecipitate with Mn 2+ cations at neutral conditions to form the manganese arsenite compound which can collapse in acidic environments, releasing Mn 2+ ions and arsenite. [119] Attracted by this fascinating property, some researchers encapsulated water-insoluble manganese arsenite compounds into hollow silica NPs (denoted as MnAsO x @SiO 2 ) to construct the arsenite loading and pHresponsive release nanosystem monitored by activatable T 1 MRI. [120,121] 

PH-RESPONSIVE NANOPLATFORMS FOR MR IMAGING
Being an advantageous non-invasive molecular imaging technology with non-ionizing radiation, non-limited penetration depth, and high spatial resolution, MRI possesses the great potential for disease diagnosis, such as peculiar tissue structure, impeded blood flow, and vascularization. [122,123] The MR signal intensity could be adjusted with contrast agents (CAs) by reducing the relaxation time of water protons to enhance the contrast effect. The main approach of tumor imaging is to employ NP-based CAs to enhance the contrast between tumor sites and normal tissues, thus surmounting the inferior tumor recognition as well as the ordinary signal-to-noise ratio. Therefore, tumor-targeting ligands which can specifically bind with tumor epitopes, could be installed onto the NPs to obtain an optimized tumor-cell specificity. [124,125] In addition, to improve the specificity of MRI, nanoplatforms that could generate pH-dependent MRI signals have also been developed. And there are mainly two approaches to construct such pH-responsive nanoplatforms for MRI. One is to encapsulate MRI CAs within pH-responsive components (e.g., block copolymers, [23,31] hydrogels, [30] CaP [106,107] ) which would be affected by protons and specifically release the CAs into tumor sites. The other approach is to employ those MRI CAs that simultaneously possess pH-responsiveness (e.g., Fe-GA, [71] LDHs, [83] MnO 2 , [91,93] and Mn(II) salts [103,113,121] ). Depending upon the magnetic susceptibilities, MRI contrast agents can be classified into two forms, that is, T 1 positive and T 2 negative.

. T  MRI contrast agents
For enhanced T 1 MRI contrast, nanomaterials should possess multiple high-spin metal cations exposed on the outside for promoted interaction with water protons in the surrounding environment. [126,127] That demands the application of smaller NPs with the higher surface-to-volume ratio. However, merely employing numerous small NPs is not consistent with the economical utilization of targeting components. As for large NPs, the metal cations hidden inside would not contribute to T 1 MRI contrast. As one of the most widely and clinically applied MRI CAs, paramagnetic gadolinium(III) chelates can improve the contrast effect via shortening the longitudinal relaxation time of the surrounding water protons beside Gd 3+ ions. [23] In spite of the broad prospect of MRI, the application of clinically approved Gd-based CAs is hindered by the inherent low efficiency of CAs, which leads to the demand for high dose administration of CAs. [64] Fortunately, the coupling of numerous Gd 3+ ions to nanoscale platforms could lead to enhanced MR relaxivity. Consequently, nanocarriers that can considerably improve the Gd capacity and enhance the T 1 relaxivity have been developed. [28,41,64] Graphene oxide (GO), which has a highly distinct area as well as various functional groups, was employed to improve the capacity for Gd-based CAs by coupling with gadolinium-labeled dendrimers in the intraparticle areas to boost its T 1 MRI contrast ability. [28] In addition, Nguyen and co-workers developed gadoliniumconjugated polymer-caged nanobins which possess a high localized concentration of Gd-based CAs and greatly enhance the relaxivity of each NP compared with small-molecule Gd CAs. [64] In another case, hydroxylated mesoporous nanosilica covered with branched polyethylenimine conjugated with Gd-DTPA was also reported, which possesses high payload of Gd and exhibits a high relaxivity per nanoparticle. [41] The easy elimination by renal filtration and lack of specific tissue distribution for Gd-based contrast agents could result in insufficient signal contrast between cancer site and its surrounding healthy tissues. [112] To address these problems, the stimulus-responsive nanoplatforms with selective signal enhancement in the tumor site need to be developed, which could potentially bring significant MR signal contrast between tumor tissue and normal tissue. Therefore, some researchers incorporated Gd-based agents into pH-sensitive nanoplatforms which possess pH-dependent MR signal enhancement property. For instance, some pH-sensitive materials (e.g. chitosan, [50] block copolymer, [23][24][25][26] liposome, [27] calcium phosphate [112] ) have been applied to encapsulate Gd-based CAs, which could efficiently release the Gd agents and significantly increase the accessibility of Gd agents to the surrounding water molecules under acidic conditions of the tumor. Consequently, the longitudinal relaxation time (T 1 ) of surrounding water molecules would be drastically shortened, leading to a positive contrast enhancement in T 1 MRI. [128] Apart from gadolinium chelates, some other Gd-based inorganic contrast agents have been employed, such as lanthanide-doped NaGdF 4 nanoparticles, [12,43,67,102] lanthanide-doped GdVO 4 , [36] Gd-doped HfO 2 , [129] Gddoped hydroxyapatite nanorods, [130] Gd 2 O 3 , [97,98,131] which exhibited significant contrast enhancement performance in tumor visualization. Among these contrast agents, it is noteworthy that the MRI contrast ability of cell membrane-coated NaGdF 4 -CaCO 3 nanocomposites (MSNPs) was originally compromised due to the spatial confinement of NaGdF 4 nanoparticles and inadequate interactions between the crystal lattices and the protons. Nevertheless, under slightly acidic conditions of the tumor, the embedded CaCO 3 NPs would produce CO 2 bubbles and subsequently dissociate the nanoconjugate, leading to the recovered MRI signals and significant tumor/muscle contrast ratio compared with commercial contrast agent, Magnevist ( Figure 3A). [102] Mn 2+ ions are representative T 1 MRI CAs with labile water exchange, long relaxation time as well as high spin number. [132] Mn-incorporated nanoplatforms mostly possess pH-responsive characteristic, which could efficiently release Mn 2+ ions at a low pH for enhanced MR imaging. For instance, Wang and co-workers encapsulated MnO nanoparticles into the silica nanoshell in which the MnO nanoparticles would be dissolved into Mn 2+ when endocytosed into the acidic compartments of tumor cells. [133] In view of the slight acidity-induced dissolution of manganese oxide nanomaterials, it can be expected that the released Mn 2+ would significantly enhance the T 1 MRI contrast effect since the released Mn 2+ ions possess larger accessibility to interact with H 2 O molecules in the surrounding environment. [95,134] Therefore, manganese oxide nanomaterials can serve as the pH-sensitive MRI contrast agents for T 1 MRI. [95,[133][134][135] In addition, Xu et al. reported the Mn-based LDH nanoparticles which have appealing T 1 MR contrast ability under slightly acidic aqueous solution (r 1 = 1.16 mM −1 s −1 at pH 7.4 while 6.82 mM −1 s −1 at pH 7.0) as well as the tumor site due to the protonation of hydroxyl groups around Mn 2+ ions, which increased the coordinated number of water molecules with Mn 2+ cations and enhanced the positive contrast in T 1 MRI ( Figure 3B). [83] Some other Mn-based nanoparticles (e.g., Mn-based LDH, [84] manganese oxide, [95,134,135] manganese salt [54,103,113,120] ) also exhibited pH-responsive property and could significantly enhance the MR signal contrast between tumor site and its surrounding healthy tissues.
Extremely small iron oxide nanoparticles (ESIONs) have drawn much attention for their capability as T 1 MRI CAs since they possess suppressed magnetization and excellent T 1 contrast ability. Meanwhile, ESIONs have good biocompatibility because the human body is capable of metabolizing iron ions, an innate element of hemoglobin. [136] To specifically deliver ESIONs into tumor tissues, many researchers have designed and constructed pH-sensitive nanocarriers (e.g., block copolymers, [34,137] mesoporous silica [65] ) which could efficiently unload ESIONs to increase the accessibility to the surrounding water molecules under acidic conditions and specifically enhance the MRI contrast of tumor.
In addition, some iron coordinated complexes can also act as T 1 MRI contrast agents [69,78] and some of them can even lead to an enhanced MR signal at a lower pH, which is mainly attributed to the increased accessibility of Fe 3+ ions to the surrounding water molecules. [71,79,80] For example, the coordinatively unsaturated Fe-containing Fe 3+ /gallic acid complex can efficiently release Fe 3+ and enhance the MR signal in the acidic environment of tumor in response to a lower pH. [71] FeOOH clusters can respond to an acidic environment and release paramagnetic Fe 3+ ions, leading to significant T 1 MRI contrast enhancement. [80] Besides, Fe 3+ /PDA complex also displayed pH-activatable MRI contrast ability. [79]

. T  MRI contrast agents
Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed for enhanced T 2 MRI contrast due to their high magnetization values. [138] Additionally, clusters of SPIONs present much better T 2 contrast effect than separate NPs. [139] Consequently, the gathering of iron oxide NPs with improved magnetization has attracted much attention owing to enhanced T 2 MRI contrast as well as the economical utilization of targeting components. Following this strategy, Yang and co-workers conjugated iron oxide nanoparticles (IONPs) with the amino-terminal fragment (ATF) peptide, a natural target ligand, to provide MRI contrast enhancement of the tumor. The results of MRI signal change demonstrated that the existence of targeting ligands greatly enhanced the T 2 MRI signal of the tumor site 1 week after administration ( Figure 4A). [140] In addition, some other nanoplatforms loaded with SPIONs and modified with a variety of targeting ligands (e.g., folic acid, [46,47,51,118,[141][142][143][144] lactoferrin, [145] peptide, [40,[57][58][59]62,146,147] antibody [148,149] ) have also been developed to facilitate the accumulation into tumor tissues and provide the contrast enhancement in T 2 MRI. Among the researches of MRI CAs, many efforts have been concentrated on the improvement of MOFs-based CAs. Those nanomaterials could easily transport paramagnetic Fe 3+ ions in large amounts which would generate enhanced contrast of the pathological tissue. [74] It is notable that MOFs of Fe 3+ (e.g., MIL-100) have been widely reported to exhibit excellent payload for anticancer drugs and T 2 MRI contrast ability, which attracted much interest in biomedical application field. [52,75,150] Apart from iron-based T 2 MRI contrast agents, our group recently reported on a manganese-based nanosystem (denoted as MnO x -SPNs) consisting of ultrathin MnO x nanosheets and semiconducting polymer nanoparticles (SPNs), which could potentially act as pH-activatable T 2 MRI contrast agent ( Figure 4B). [151] More specifically, MnO x nanosheets would dissolve into Mn 2+ , Mn 3+, and Mn 4+ under acidic conditions, in which the Mn ions with higher valance states would be probably reduced into Mn 2+ by SPNs. Moreover, when Mn 2+ combined with bovine serum albumin (BSA), the Mn-BSA exhibited an even better T 2 contrast effect, thus achieving the multi-step signal amplification.

. T  -T  dual modal MRI contrast agents
Despite every MRI mode having its own advantage, sometimes a single MRI mode cannot meet the high diagnostic requirements because each form of CAs has its inherent shortcomings and the medical diagnostic results could be deceptive merely by employing the single imaging modality. [152] For instance, the T 2 negative signals obtained with CAs are frequently confused with the signals from metal deposits, bleeding, or calcification. [153] This restriction can be mended by integrating T 1 and T 2 MR imaging modalities into a single nanoplatform since it could produce diagnostic results with great accuracy benefiting from high tissue resolution provided by T 1 MRI as well as high practicability on detecting lesions provided by T 2 MRI. [154] Consequently, MRI contrast agents with T 1 -T 2 dual modal functions have attracted considerable interest.
Recently, many T 1 -T 2 dual modal CAs have been developed, such as gadolinium-doped IONPs, [155] which exhibited excellent T 1 -T 2 dual modal MR contrast enhancement both in vitro and in vivo. Wu Figure 5A). [156] In addition, some other researchers have successfully integrated SPIONs and Mn-based agents into a single nanoplatform acting as T 2 and T 1 contrast agents respectively. [115,157] Intriguingly, both dual modal contrast agents presented enhanced T 1 and T 2 MR signals under acidic conditions of tumor due to the pH-dependent release of T 1 MRI contrast agents. For instance, Shi et al. realized the co-integration of SPIONs and MnO x NPs onto exfoliated graphene oxide nanosheets (denoted as Fe 3 O 4 /MnO x -GO) through a facile two-step double redox strategy, in which the MnO x nanoparticles could be dissolved into Mn 2+ under acidic conditions. Notably, both T 1 and T 2 MR signal enhancements were observed both in vitro and in vivo in an acidic environment ( Figure 5B). [29] In another case, an intelligent nanoflower composite with superparamagnetic Fe 3 O 4 nanoclusters as the core and MnO 2 nanosheets as the outer shell was also developed for T 1 -T 2 dual modal imaging. [158] Apart from integrating two different kinds of contrast agents into one nanoplatform, some other researchers have applied one single kind of nanomaterial (e.g., R-PtWMn, [159] Prussian blue, [76,88] NaMnF 3 , [39] Mn 3 [Co(CN) 6 ] 2 [77] ) which

 PH-RESPONSIVE THERANOSTIC NANOPLATFORMS FOR MRI-GUIDED SINGLE MODE THERAPY
Nowadays, cancer is one of the most severe illnesses menacing physical health of citizens. [42] To fight against cancer, a wide range of treatment modes have emerged, such as chemotherapy, radiotherapy, PDT, chemodynamic therapy, hyperthermia, immunotherapy, etc. Notably, all the therapeutic modes discussed below were carried out with pHresponsive nanoplatforms and under MRI guidance, which to some degree improved the specificity and accuracy of the treatment.

. Chemotherapy
Among the various treatment approaches, chemotherapy is essential because it can be easily employed in diverse types of cancers. Fortunately, the current chemotherapeutic drugs are generally effective to kill various types of tumor cells. [160] However, the primary issue in the clinical chemotherapy is the fatal side effects of the anticancer drugs which are induced by the non-specific attack of the drug molecules toward normal cells. [160] A reasonable method to overcome these shortcomings is targeted delivery of chemotherapeutic drugs specifically into tumor cells. By taking advantage of the slightly acidic characteristic in tumor tissues, nanotechnology-mediated pH-responsive drug delivery systems have emerged. For example, Shen and co-workers developed the pH-responsive nanoclusters (USIO NCs/DOX@CM) which could be dissociated into ultrasmall IONPs with dynamic T 2 /T 1 MRI and unload the anticancer drug DOX efficiently. Moreover, through the ultrasound-targeted microbubble destruction (UTMD) technology, the tumor accumulation and penetration of USIO NCs/DOX@CM would be enhanced, leading to significant tumor suppressive effect. Notably, pH-triggered disassembly of nanoplatforms to release drug and brighten T 1 MRI, thus MRI signals were used to monitor the accumulation and release of drug. Compared to the free DOX treatment, the USIO NCs/DOX@CM-UTMD treatment showed great biosafety with no body weight loss recorded ( Figure 6A). [161] Additionally, other pH-responsive drug delivery systems such as mesoporous silica, [41,65,67,80,162] MOFs, [74,87,163] polymeric micelles, [34,78,164,165] nanohydrogel, [36,166] MnO 2 nanosheets, [91,167] graphene oxide [28] and liposomes [27,62] have also been developed, showing huge application potential in cancer treatment. Moreover, the therapeutic process could be monitored by MRI, which further improves the specificity of cancer treatment.
It's well-confirmed that each type of anticancer drug has its distinctive growth inhibition mechanism through the period of cell cycle. However, the application of one type of chemotherapeutic drugs is insufficient for the treatment of tumors because their complicated structure and heterogeneity could lead to significant drug resistance. Therefore, the co-delivery of multi chemotherapeutic drugs through nanoplatforms has been developed and exhibited greater toxicity toward various tumor cells on account of their different anticancer activity through different period of tumor development than the single drug. [173] Qiao et al. encapsulated DOX, camptothecin, and combretastatin A4 in the same nanoparticles which could be effectively released to the corresponding active sites in time and space for tumor combined chemotherapy. [42] Additionally, the combinations of DOX and rhodamine B, [174] DOX, and colchicine [28] were also employed for synergistic chemotherapy.

. PDT
As a clinically approved non-invasive therapeutic method, PDT utilizes a photosensitizer, oxygen molecules, and an appropriate exciting light through the production of cytotoxic reactive oxygen species (ROS) to destroy biomolecules such as DNAs and biological membranes inside tumor cells. [54] The primary obstacle to PDT is hypoxia in the TME. [96] It is well-established that the rapid-growing tumor cells as well as the abnormal and generally twisted blood vessels inside solid tumors are accountable for inadequate O 2 supply, higher H 2 O 2 level, and acidity in the solid tumors. [175] To ameliorate the oxygen-deprived condition and further improve the curative effect of PDT, many efforts have been made to construct nanoplatforms that could realize self-sufficiency of O 2 , delivery, or generation of abundant O 2 inside the tumor to overcome hypoxia. Going down this trend, several researchers discovered that manganese dioxide nanomaterials possess TME-responsive and TME-modulating properties, which could catalyze the decomposition of H 2 O 2 into oxygen and water in the TME. [92] Consequently, MnO 2 nanomaterials can act as the O 2 -producing and H 2 O 2 -depleting agent for the improvement of the PDT performance. Based on this finding, Yang and co-workers developed an intelligent pH-controllable and H 2 O 2 -responsive nanosystem (hMUC) based on honeycomb MnO x NPs and chlorin e6 (Ce6)sensitized up-conversion nanoparticles (UCNPs). When irradiated by tissue-penetrable 808 nm laser, UCNPs would emit visible photons with higher-energy which could be absorbed by Ce6 to produce cytotoxic ROS, thereby inducing PDT process naturally and suppressing tumor growth prominently ( Figure 6B). [96] Similarly, Ge et al. fabricated carbon dots/manganese dioxide nanocomposites, which exhibited enhanced ROS generation and significantly promoted PDT efficacy. [176] In the meantime, the treatment of cancer would be more precise and specific under the guidance of MRI. [96,176] In addition to the strategy of improving tumor hypoxia, the PDT efficacy could also be enhanced through blocking the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway. [54] Based on this strategy, Zhang and co-workers applied photosensitizer and acriflavine(ACF)loaded porous manganese phosphate (PMP) NPs as the photoactivable synergistic system which imparts ROS triggered cytotoxicity in coordination with HIF-1α /VEGF inhibitor which prevents tumor growth and development as well as treatment escape signaling pathway. Upon the stimulus of the tumor acidic microenvironment, the PMP NPs would disintegrate to release Mn 2+ for MRI and the photosensitizer Ce6 would be released to produce ROS under irradiation while ACF blocks the HIF-1α /VEGF pathway during the burst release of VEGF in tumor triggered by PDT, leading to improved curative effect. [54]

. Photothermal therapy
As a promising therapeutic strategy for cancer, photothermal therapy (PTT) has attracted much interest on account of its minimal damage to healthy tissues and great ablation efficiency, which is generally induced by near-infrared (NIR) laser to produce heat for the thermal ablation of the tumor in situ. [177][178][179] For the purpose of optimizing the PTT efficacy, diverse photothermal-transducing agents have F I G U R E  pH-responsive nanoplatforms for (A) photothermal therapy. The nanoplatform (MnO x /Ti 3 C 2 −SP) is based on soybean phospholipid (SP)-modified MnO x /Ti 3 C 2 nanosheets. Schematic illustration of MnO x /Ti 3 C 2 −SP nanosheets as the photothermal agents for cancer cell ablation. The magnetic resonance imaging (MRI) and PTT performance of MnO x /Ti 3 C 2 −SP. Reproduced with permission. [135] Copyright 2017, American Chemical Society. (B) Chemodynamic therapy. The nanoplatform (FePt@FeO x @TAM-PEG) is based on core-shell structured FePt@FeO x and pH-sensitive drug tamoxifen (TAM). Schematic illustration of acidity-unlocked FePt@FeO x @TAM-PEG with positive feedback loop promoting Fenton-like reactions for self-boosting tumor specific chemodynamic therapy. The MRI and CDT performance of FePt@FeO x @TAM-PEG. Reproduced with permission. [181] Copyright 2021, Wiley-VCH GmbH. (C) Immunotherapy. The nanoplatform (NC-aP) is based on PD-1 antibody-conjugated Fe 3 O 4 nanoclusters. Schematic illustration of magnetic nanoclusters armed with PD-1 antibody improved adoptive T cell therapy for solid tumors. The therapeutic outcomes of NC-aP under magnetic field and other groups. Reproduced with permission. [184] Copyright 2019, American Chemical Society. been employed including 2D titanium carbide (Ti 3 C 2 ), [135] PDA, [79,104] and polypyrrole. [31] Particularly, MRI-guided PTT has exhibited great potential as a promising theranostic strategy for clinical application. MRI can recognize the location and size of the tumor while the NIR laser can be specifically applied onto the tumor site. For instance, Chen et al. designed the MnO x /Ti 3 C 2 nanocomposite (MnO x /Ti 3 C 2 -SP) for pH-activated MRI and PTT. Under the NIR light irradiation for 10 min, the tumor temperature increased significantly from 25 • C to 60 • C with the injection of MnO x /Ti 3 C 2 -SP, which is high enough to destroy tumor cells and suppress tumor growth ( Figure 7A). [135] Moreover, by taking advantage of pH-dependent MR contrast enhancement, a more precise and satisfactory theranostic process would be obtained.
Consequently, pH-activatable MRI-guided PTT could realize the optimized specificity and minimal damage to normal tissues. [31,79,104,135]

. Chemodynamic therapy
Chemodynamic therapy (CDT), as an emerging alternative therapeutic modality, employs CDT agents to transform H 2 O 2 into the hydroxyl radical (⋅OH), the most damaging ROS through Fenton/Fenton-like reactions, thereby triggering cell apoptosis and necrosis. [99,180] Based on this treatment strategy, our group recently encapsulated core-shell structured FePt@FeO x NP and pH-sensitive drug tamoxifen (TAM) simultaneously into polymeric matrix (denoted as FePt@FeO x @TAM-PEG) for tumor-specific MRI-guided CDT. Notably, the catalytic activity of FePt@FeO x is initially blocked in normal tissues. However, the TAM could be protonated and released under acidic conditions of tumor, which is capable of inhibiting mitochondrial complex I and thereby upregulating the lactate content and intracellular H + . Consequently, FePt@FeO x nanocatalyzers would be more efficiently released and exert the improved Fenton-like reaction under more acidic conditions, which significantly suppressed the growth of tumor ( Figure 7B). [181] Additionally, Hou et al. fabricated the core-shell NPs with a core of magnetic Fe 5 C 2 and a shell of pH-responsive iron oxide coating, which could disintegrate and release ferrous ions under acidic conditions to convert H 2 O 2 into ⋅OH radicals, thus efficiently inhibiting the proliferation of tumor cells. Furthermore, the dissolution of iron oxide coating simultaneously decreased the T 2 MR signal and increased the T 1 MR signal, and this T 2 /T 1 switching feature offers opportunity for visualizing the release of Fe 2+ and the production of ROS for the surveillance of tumor treatment. [99]

. Immunotherapy
Cancer immunotherapy has markedly shifted the paradigm of therapeutic strategy for cancer in the past two decades. [182] Among the immunotherapeutic methods, an advantageous approach is to directly inject immunoadjuvants into the tumor sites to in situ induce cancer vaccination following immunogenic cell death treatments. [183] The cancer vaccination attempts to convey the local tumor antigens to antigen presenting cells, especially to the dendritic cells, by a more effective pattern for the purpose of priming the antigenspecific CD8+ T cells and realizing the production of CD8+ T cells in abundance to destroy tumor cells. [183] Based on this strategy, Wang et al. employed the pH-responsive hollow Gd 2 O 3 nanospheres, which tend to conjugate with various biomolecules due to the existence of surface charge, to efficiently deliver F-OVA, a model tumor antigen into tumor tissues for immunotherapy under the surveillance of pH-dependent MRI. [98] In addition, to promote the performance of adoptive T-cell therapy, an immune-based approach, Xie et al. developed magnetic nanoclusters conjugated with PD-1 antibodies through pH-responsive benzoic-imine bond (denoted as NC-aP), which could bind with effector T cells (e.g., CTLs, TILs) owing to their PD-1 expression. Subsequently, both effector T cells and NC-aP could be recruited into tumor sites under external magnetic field with MRI guidance. In an acidic environment of the tumor, the PD-1 antibody would be released for PD-1 blocking, which could work in a synergistic manner with the adoptive T cells. As a result, when exposed to an external magnetic field, the development of E.G7 tumor model would be completely suppressed in the CTL:NC-aP(m) group, and the development of 4T1 tumor model would be almost totally inhibited in the TIL:NC-aP(m) group ( Figure 7C). [184] 

PH-RESPONSIVE THERANOSTIC NANOPLATFORMS FOR MRI-GUIDED COMBINED THERAPY
Owing to the unsatisfactory curative effects obtained from single mode therapy, a synergistic treatment modality combining different drugs and mechanisms with improved performance for cancer therapy is exceedingly attractive. Furthermore, with the incorporation of MRI contrast agents, these pH-responsive nanoplatforms exhibit even more precise and satisfactory therapeutic effects under the guidance of MRI.

. Chemotherapy/PTT
The combination of PTT and chemotherapy has been widely established to be capable of achieving satisfactory therapeutic effects, [69,75,76,185] since chemotherapeutic drugs can be efficiently unloaded under high temperature and constantly generate the chemotherapeutic effect for the long term. [147,[186][187][188] Additionally, when combined with chemotherapy, PTT could cooperatively improve the treatment effect, e.g., promotion of cell membrane permeability, enhanced accumulation of the NPs in tumor sites, and improvement of drug toxic effect. [75] Furthermore, when combined with MRI-based diagnostics, the precision, and specificity of the synergistic treatment would be significantly improved. In order to take advantage of these merits, Zhu and co-workers constructed the redox-sensitive disulfide linkers equipped Fe 3 O 4 @PDA NPs coated by hyaluronic acid, which were subsequently deposited with the chemotherapeutic drug, DOX. Under the irradiation of NIR light, PTT would be activated to produce heat for the thermal ablation of tumors. Meanwhile, the drug release would be induced by acidity, glutathione, and high temperature, thus realizing the synergistic application of PTT and chemotherapy. [189] Additionally, some researchers discovered that hyperthermia (T > 46 • C) triggered by PTT would aggravate the hypoxia level in TME, leading to overexpressed hypoxia inducible factor-1 (HIF-1). [190] It is noteworthy that banoxantrone (AQ4N) is a novel bio-reductive prodrug showing excellent anticancer activity under hypoxic conditions through an enzymatic process via bio-reduction to its metabolite AQ4. [191] Based on this finding, Liu and co-workers integrated the pH/hypoxia-inducible Fe(III)-AQ4N prodrugs and semiconducting polymer dots (denoted as Mn-APPMSF), in which the Fe(III)-AQ4N prodrug would be cleaved under acidic conditions of tumor, for programmable triggered and MRI-guided photothermal-chemotherapy. Upon NIR laser irradiation, the tumor temperature of Mn-APPMSF injected mice could rise about 20 • C in 5 min, which would lead to efficient cancer cell destruction via local hyperthermia and aggravate the tumor hypoxia level. Interestingly, the enhanced hypoxia could further accelerate the reduction of AQ4N to greatly improve the curative effects and significantly inhibit tumor growth ( Figure 8A). [190]  Reproduced with permission. [190] Copyright 2018, The Royal Society of Chemistry. (B) Chemotherapy and magnetic hyperthermia. The nanoplatform (γ-SD/PLL) is based on covalent organic frameworks-coated γ-Fe 2 O 3 NPs. Schematic representation of magnetically induced heat-and acid-triggered Dox release from γ-SD/PLL in conditions that mimic cancer cell physiology. The magnetic resonance imaging performance, DOX release profiles, and therapeutic outcomes of γ-SD/PLL. Reproduced with permission. [192] Copyright 2020, American Chemical Society.

. Chemotherapy/magnetic hyperthermia
The combination of chemotherapy and magnetic hyperthermia (MH) is under research for the effective alleviation of tumors. [15,29,173,192] MH possesses great capability for heat-activated ablation of tumor tissues at 43-45 • C under external AC magnetic field. Moreover, it's able to enhance the drug toxicity in drug-resistant cancer cells. [173] Fe 3 O 4 nanoparticles have been widely employed as the nanoconverter for MH to produce localized heat from the input of external magnetic energy as a result of their magneticallyinduced hyperthermia capability. [15,173] To further improve the hyperthermia capability of magnetic nanomaterials, the magnetic iron oxide (γ-Fe 2 O 3 ) NPs coated covalent organic frameworks (COFs) were also applied as MH agents to effectively generate more heat (48 • C) when exposed to the AC magnetic field (AMF) because the porous structure of COFs could facilitate the heat conduction. Moreover, the nanoplatform (denoted as γ-SD/PLL) exhibited efficient capacity for anticancer drug Doxorubicin and would disintegrate in the acidic environment for rapid drug release and MRI signal production, which achieved combined chemo-thermotherapy under the surveillance of MRI ( Figure 8B). [192] Additionally, Shi et al. integrated magnetic Fe 3 O 4 NPs onto exfoliated GO nanosheets, which possess the high heat transfer ability/thermal conductivity for synergistic improvement of MH, to construct a nanosystem that can be applied for MH upon exposure to external magnetic field. Meanwhile, GO nanosheets can efficiently load aromatic anticancer drugs (e.g., DOX) through supramolecular π stacking as well as MnO x NPs, which both exhibited pH-responsive property, thus making this nanosystem capable for pH-activatable MRI-guided synergistic chemo-thermotherapy. [29] . Chemotherapy/PDT Despite the cooperative therapy of PDT and chemotherapy being much more effective for cancer therapy than monotherapies, premature release of anticancer drugs and  of  hypoxia in the TME may lead to systemic toxicity and inferior therapeutic effects. [193] To address these problems, Meng et al. developed an intelligent nanoflower composite with multistage pH/H 2 O 2 /GSH-responsive characteristics which fully exploited TME features to achieve the controlled release of anticancer drugs into tumor sites and maximum synergistic curative effects. The inner polyphosphazene containing (bis-(4-hydroxyphenyl)-disulfide) is pH-and GSHresponsively biodegradable to unload the chemotherapeutic drug curcumin (CUR) and photosensitizer Ce6 in the TME. With MnO 2 nanosheets as the outer shell, O 2 concentration could be elevated by catalytic decomposition of H 2 O 2 and Mn 2+ ions could be released for T 1 -MRI in the presence of acid and GSH. Therefore, with specific release of drugs, the relief of hypoxia, and the consumption of antioxidant, this TME-responsive cancer theranostic nanoplatform achieved significant optimization of chemotherapy and PDT under the guidance of MRI. [158] Instead of overcoming tumor hypoxia, another attractive strategy that utilizes the unfavorable PDT-induced hypoxia to activate prodrug for supplementary chemotherapy has been proposed. [194] Following this strategy, Fan and co-workers developed the tandem activated theranostic nanoplatform (denoted as (UCNP@PFNS/AQ4N)@MnCaP) which utilized semiconducting polyelectrolyte-based zwitterionic photosensitizer (PFNS) modified UCNPs as the core and pH-sensitive Ca 3 (PO 4 ) 2 as the shell. Notably, this nanoplatform could realize different tumor distributions of photosensitizer (PFNS) and hypoxia-activated prodrug (AQ4N) for amplified combination therapy. Furthermore, due to the existence of the pH-responsive outer shell, the doped Mn 2+ ions and incorporated prodrugs would be specifically released under acidic conditions of the tumor, thus achieving the pH-activatable T 1 -MRI and improving the precision of the combined therapy ( Figure 9A). [111] . Chemotherapy/chemodynamic therapy To integrate chemotherapy and chemodynamic therapy into a single system, Zhu et al. constructed bufalin-loaded pH-responsive hollow MnO 2 NPs for chemo-chemodynamic synergistic therapy under the guidance of MRI. [90] Additionally, in a recent work of our group, we developed the DOX-loaded iron oxide nanoclusters (denoted as Dox-CACN) via DNA-programmed self-assembly. It is noteworthy that only upon co-activation by dual stimuli of adenosine triphosphate (ATP) and acid in TME, the catalytic activity of the nanoplatform would be upregulated for specific CDT. Besides, ATP-triggered disassembly of nanoclusters under acidic conditions resulted in the release of DOX and switchable T 2 /T 1 MRI, which was correlated with ROS generation and Dox release. As a result, both intratumorally (i.t.) and intravenously (i.v.) injected Dox-CACN markedly suppressed tumor development and minimized unwanted side effects through the co-activation strategy and the guidance of switchable MRI ( Figure 9B). [128] . Chemodynamic therapy/limotherapy A multifunctional theranostic nanoplatform (denoted as MCDION-Se) combing CDT and limotherapy under the guidance of MRI was developed on the basis of nanoselenium (nano-Se)-coated MnCO 3 -deposited nanoparticles. [195] The pH-dependent decomposition of MnCO 3 would cause abundant release of Mn 2+ ions which could catalyze H 2 O 2 into hydroxyl radicals (⋅OH) through the Fenton-like reaction, efficiently inducing apoptosis of the tumor cells. Furthermore, the pH-dependent release of Mn 2+ ions could produce enhanced T 1 MR signal contrast under acidic conditions. Besides, nano-Se could dramatically activate superoxide dismutase (SOD) and promote the production of superoxide anion radicals (SOARs) in tumor tissues. Subsequently, a large number of H 2 O 2 was generated through SOD catalysis of SOARs, further improving CDT efficacy. In the meantime, the nano-Se and Mn 2+ could inhibit the production of ATP, thus starving tumor cells. As can be seen, the MCDION-Se exhibited the best tumor inhibition efficiency and relatively high MRI signal change ratio 45 min after administration ( Figure 10A). [195] . Chemotherapy/radiotherapy/PTT In a radiotherapy (RT) process, X-ray or γ-ray is employed to activate water molecules to generate ROS, which can cause oxidative damage to proteins, lipids as well as DNAs and subsequently induce cell apoptosis. [196] Nevertheless, RT has several drawbacks such as unclear side effects, resistance of radiation, and variation of radiation sensitivity for different individuals. [196] In addition, the multiple drug resistance of the tumor could arise from the long-term chemotherapy, which greatly impedes the curative effects. [197] Fortunately, PTT is in the position to reduce drug resistance via hindering DNA repair, disrupting signal transduction, and denaturing cytoplasmic protein, which exhibits significant synergism with chemotherapy and radiotherapy. [197,198] Figure 10B). [129] Additionally, a cisplatin-loaded, PDA-coated multi-functional theranostic system was also developed for MRI-guided combined therapy due to the Schematic representation of (UCNP@PFNS/AQ4N)@MnCaP for synergetic PDT and chemotherapy under magnetic resonance imaging (MRI) guidance. The MRI and therapeutic outcomes of (UCNP@ PFNS/AQ4N)@MnCaP. Reproduced with permission. [111] Copyright 2019, Elsevier Ltd. (B) Chemotherapy and chemodynamic therapy. The nanoplatform (Dox-CACN) is based on DOX-loaded iron oxide nanoclusters via DNA-programmed self-assembly. Schematic representation of dual key co-activated nanoplatform for switchable MRI monitoring ferroptosis-based synergistic therapy. The therapeutic outcomes of Dox-CACN and other groups. Reproduced with permission. [128] Copyright 2022, Elsevier Inc. simultaneous chemotherapeutic effect and radiosensitization of cisplatin and photothermal effect of PDA. [40] 

CONCLUSION AND PROSPECTS
The acidic characteristic of the tumor site provides more motivation for tumor growth, invasion, and metastasis, but also offers a series of opportunities for cancer-specific theranostic strategies. In this review, we summarized the pH-responsive theranostic nanoplatforms with simultaneous diagnostic and therapeutic abilities. These nanoplatforms have drawn much attention in the field of nanomedicine because they provided great opportunity in the combat with cancer. On account of passive and active tumor targeting, theranostic nanoplatforms with pH-responsiveness are able to deliver MRI contrast agents and therapeutic agents efficiently to the malignant tumor sites for MRI-guided cancer therapy. The different design strategies applied to construct pH-responsive theranostic nanoplatforms are presented in Table 1 (See Scheme 1). While significant progress has been made in the development of MRI-based theranostic nanoplatforms which exhibited superb properties and undeniable potential in the grow-ing era of personalized medicine, several challenges and obstacles still hinder the transition from bench to bedside, with few nanoplatforms undergoing clinical trials. One challenge in the clinical application of theranostic agents is the demand for high doses to achieve the desired diagnostic and therapeutic effects, which may bring unsafe and toxic problems. Besides, the multifunctional theranostic nanoplatforms typically require complicated synthesis processes and may cause premature release of cargo, which can lead to unwanted damage to healthy tissues. In addition, with the single stimulus response of merely low pH, the precision and specificity of the nanoplatform for theranostics could be undermined due to the existence of acidic compartments (e.g., lysosome, endosome) in normal cells. Consequently, it is appealing to design and develop dual/multiple stimuli-responsive (e.g., hypoxia, acidosis, redox, ATP) nanoplatforms to realize more precise and specific diagnosis and therapy of tumors with minimized unwanted damage to the healthy tissues.
The incorporation of MRI as a diagnostic method has brought great convenience for the treatment of cancer. However, the MRI outcomes and the therapeutic effects seem to be cut apart with unclear correlation between them. Therefore, it is appealing to design and develop a theranostic nanoplatform F I G U R E   pH-responsive nanoplatforms for combined therapy. (A) Chemodynamic therapy and limotherapy. The nanoplatform (MCDION-Se) is based on nanoselenium (nano-Se)-coated MnCO 3 -deposited nanoparticles. Schematic illustration of the cascade reaction of MCDION-Se in the intracellular environment. The magnetic resonance imaging (MRI) and therapeutic outcomes of MCDION-Se and other groups. Reproduced with permission. [195] Copyright 2019, Elsevier Ltd. (B) Chemotherapy, radiotherapy, and photothermal therapy. The nanoplatform (Gd 2 Hf 2 O 7 @PDA@PEG-Pt-RGD) is based on polydopamine (PDA)-modified and cisplatin-loaded Gd 2 Hf 2 O 7 NPs. Schematic illustration of Gd 2 Hf 2 O 7 @PDA@PEG-Pt-RGD for MRI-guided synergistic therapy. The MRI and therapeutic outcomes of Gd 2 Hf 2 O 7 @PDA@PEG-Pt-RGD and other groups. Reproduced with permission. [129] Copyright 2020, American Chemical Society.
in which the MRI signal intensities could reflect the therapeutic effects in real time with a direct correlation. Furthermore, the biosafety of the MRI CAs remains a big concern. For instance, exposure to Gd-containing CAs was associated with the development of nephrogenic systemic fibrosis in patients with renal insufficiency. [199] Although Mn-based CAs possess improved biocompatibility over Gd-based CAs, the toxicity problem still existed. [136] Compared to Mn 2+ , Fe 3+ is considered more biocompatible because the human body is capable of metabolizing iron ions, an innate element of hemoglobin. Thus, we assume that Fe-based CAs might be a more suitable candidate for further clinical use. Besides, for the next generation of pH-responsive MRI CAs, it would be beneficial to design smart MRI CAs, which could produce a larger variation of signal intensity in response to a more subtle pH gradient. In this case, it might be able to realize the precise imaging of subcellular structures which possess the different ranges of pH variation. In addition, single MRI modality is limited by its poor sensitivity. Thus, it can be combined with other imaging modalities (e.g., optical imaging, positron emission tomogra-phy, or single-photon emission computed tomography) which possess the desired sensitivity to obtain the imaging results with high accuracy.
In the end, translating basic research into clinical use requires the demonstration of improved therapeutic efficacy over the current therapies and sufficient biocompatibility. There is increasing evidence that the synergistic strategy combining different drugs and mechanisms with improved curative effects is extremely appealing to combat the heterogeneous and multi-drug resistant tumors. Consequently, the multifunctional theranostic nanoplatforms which exhibited considerable values for biomedical applications due to their superior properties and potential for clinical use, are well suited for this purpose. We believe that, with the constant optimization of pH-responsive theranostic nanoplatforms, the diagnostic and therapeutic capabilities would be improved while the side effects produced during the treatment procedure would be minimized as much as possible. Although breakthroughs in this area largely rely on the collaboration between different fields of knowledge, the future of theranostic nanoplatform is promising and we anticipate that more attempts based on this would be made in the near future.

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflict of interest.

A C K N O W L E D G M E N T S
This work was supported by the National Natural Science Foundation of China (grants U21A20287, 51872088), the Science and Technology Project of Hunan Province (2020RC3022; 2020SK2014), and the Shenzhen Science and Technology Program (JCYJ20210324140205013).