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Inorganic nanomaterials that have inherently exceptional physicochemical properties (e.g., catalytic, optical, thermal, electrical, or magnetic performance) that can provide desirable functionality (e.g., drug delivery, diagnostics, imaging, or therapy) have considerable potential for application in the field of biomedicine. However, toxicity can be caused by the long-term, non-specific accumulation of these inorganic nanomaterials in healthy tissues, preventing their large-scale clinical utilization. Over the past several decades, the emergence of biodegradable and clearable inorganic nanomaterials has offered the potential to prevent such long-term toxicity. In addition, a comprehensive understanding of the design of such nanomaterials and their metabolic pathways within the body is essential for enabling the expansion of theranostic applications for various diseases and advancing clinical trials. Thus, it is of critical importance to develop biodegradable and clearable inorganic nanomaterials for biomedical applications. This review systematically summarizes the recent progress of biodegradable and clearable inorganic nanomaterials, particularly for application in cancer theranostics and other disease therapies. The future prospects and opportunities in this rapidly growing biomedical field are also discussed. We believe that this timely and comprehensive review will stimulate and guide additional in-depth studies in the area of inorganic nanomedicine, as rapid in vivo clearance and degradation is likely to be a prerequisite for the future clinical translation of inorganic nanomaterials with unique properties and functionality. [ABSTRACT FROM AUTHOR]

The acidic tumor microenvironment (TME), which mainly results from the high glycolytic rate of tumor cells, has been characterized as a hallmark of solid tumors and found to be a pivotal factor participating in tumor progression. Recently, due to the increasing understanding of the acidic TME, it has been shown that the acidic TME could be utilized as a multifaceted target during the design of various pH-responsive nanoscale theranostic platforms for the precise diagnosis and effective treatment of cancers. In this article, we will give a focused overview on the latest progress in utilizing this characteristic acidic TME as the target of nano-theranostics to enable cancer-specific imaging and therapy.The future perspectives in the development of acidic TME-targeting nanomedicine strategies will be discussed afterwards. [ABSTRACT FROM AUTHOR]

The fabrication of functional nanoparticles with unique ultra-sensitivity to endogenous tumor microenvironment (TME) is of great significance for their improved theranostic performance and easy excretion out of the body, which has not been realized among diverse nano-sized photothermal agents for photothermal therapy (PTT) of tumor. In this work, we report on the synthesis of 2D ultrathin MnO 2 nanosheets for highly efficient PTT against tumor with ultra-sensitivity to endogenous TME. These ultrathin 2D MnO 2 nanosheets show the intriguing characteristic of disintegration and releasing of Mn 2+ in response to the mild acidic condition and elevated reducing microenvironment of TME, which has successfully realized the pH- and reducing-responsive T 1 -weighted magnetic resonance imaging of tumor. Importantly, the high PTT efficiency of 2D MnO 2 nanosheets responsive to exogenous NIR irradiation has been systematically demonstrated both in vitro and in vivo for suppressing the tumor growth. This first report on the exploring of TME-sensitive photothermal agents with concurrent diagnostic and therapeutic (theranostic) functions significantly broadens the biomedical application of 2D functional biomaterials, which also promotes the further potential clinical translations of nano-sized photothermal agents. [ABSTRACT FROM AUTHOR]

Multifunctional biodegradable inorganic theranostic nano-agents are of great interest to the field of nanomedicine. Upon lipid modification, VS2 nanosheets could be converted into ultra-small VS2 nanodots encapsulated inside polyethylene glycol (PEG) modified lipid micelles. Owing to paramagnetism, high near-infrared (NIR) absorbance, and chelator-free 99mTc4+ labeling of VS2, such VS2@lipid-PEG nanoparticles could be used for T1-weighted magnetic resonance (MR), photoacoustic (PA),and single photon emission computed tomography (SPECT) tri-modal imaging guided photothermal ablation of tumors. Importantly, along with the gradual degradation of VS2, our VS2@lipid-PEG nanoparticles exhibit effective body excretion without appreciable toxicity. The unique advantages of VS2 nanostructures with highly integrated functionalities and biodegradable behaviors mean they are promising for applications in cancer theranostics. [ABSTRACT FROM AUTHOR]

Nanoscale coordination polymers (NCPs) self-assembled from metal ions and organic bridging ligands exhibit many unique features promising for applications in nanomedicine. In this work, manganese dioxide (MnO2) nanoparticles stabilized by bovine serum albumin are encapsulated by NCP-shells constructed based on high-Z element hafnium (Hf) ions and c,c,t-(diamminedichlorodisuccinato)Pt(IV) (DSP), a cisplatin prodrug. After further modification with polyethylene glycol (PEG), the formed BM@NCP(DSP)-PEG can simultaneously serve as a radio-sensitizer owing to the strong X-ray attenuation capability of Hf to enhance radiotherapy, as well as a chemotherapeutic agent resulting from the reduction-induced release of cisplatin. Meanwhile, the in situ generated oxygen resulting from MnO2-triggered decomposition of tumor endogenous H2O2 will be greatly helpful for overcoming hypoxia-associated radio-resistance. Upon intravenous injection, BM@NCP(DSP)-PEG shows efficient tumor homing as well as rapid renal excretion, as illustrated by magnetic resonance imaging and confirmed by biodistribution measurement. Notably, an excellent in vivo tumor growth inhibition effect is observed with BM@NCP(DSP)-PEG nanoparticles after the combined chemoradiotherapy treatment. Therefore, the NCP-based composite nanoparticles with inherent biodegradability and no appreciable in vivo toxicity may be a unique type of multifunctional nanoplatform responsive to different parameters in the tumor microenvironment, promising for cancer theranostics with great efficacy. [ABSTRACT FROM AUTHOR]

Despite extensive use of radiotherapy in cancer treatment, there has been huge demand to improve its efficacy and accuracy in tumor destruction. To this end, nanoparticle-based radiosensitizers, particularly those with high-Z elements, have been explored to enhance radiotherapy. Meanwhile, imaging is an essential tool prior to the individual planning of precise radiotherapy. Here, hollow tantalum oxide (H-TaOx) nanoshells are prepared using a one-pot template-free method and then modified with polyethylene glycol (PEG), yielding H-TaOx-PEG nanoshells for imaging-guided synergistically enhanced radiotherapy. H-TaOx-PEG nanoshells show strong intrinsic binding with metal ions such as Fe3+ and 99mTc4+ upon simple mixing, enabling magnetic resonance imaging and single photon emission computed tomography imaging, respectively, which are able to track in vivo distribution of those nanoshells and locate the tumor. With mesoporous shells and large cavities, those H-TaOx-PEG nanoshells show efficient loading of 7-ethyl-10-hydroxycamptothecin (SN-38), a hydrophobic chemotherapeutic drug. By means of the radiosensitization effect of Ta to deposit X-ray energy inside tumors, as well as SN-38-induced cell cycle arrest into radiation-sensitive phases, H-TaOx-PEG@SN-38 can offer remarkable synergistic therapeutic outcome in the combined chemoradiotherapy. Without appreciable systemic toxicity, such hollow-TaOx nanostructure may therefore find promising applications in multimodal imaging and enhanced cancer radiotherapy. [ABSTRACT FROM AUTHOR]

Metastasis is directly or indirectly responsible for the majority of cancer deaths. Anti-metastasis treatment is thus the key to cure cancer. Recent development in nanomedicine has shown great promise for tackling cancer metastasis. In recent years, nanoparticle-based drug delivery systems have been extensively explored for improving cancer treatment, showing the ability to reduce the risk of tumor metastasis compared with conventional chemotherapy. Photothermal therapy, by employing nano-theranostic agents, has also been found to be able to inhibit lymphatic tumor metastasis. Moreover, the post-immunological effects of certain types of nano-therapies may also be utilized to treat tumor metastasis, presenting an exciting new avenue towards successful cancer treatment. In this review article, we would like to summarize the latest research advances in the development of various emerging nanomedicine approaches for cancer metastasis treatment, and discuss future prospects in this emerging field as well as the clinical translation potential of these techniques. [ABSTRACT FROM AUTHOR]

Multifunctional theranostic agents have become rather attractive to realize image-guided combination cancer therapy. Herein, a novel method is developed to synthesize Bi2Se3 nanosheets decorated with mono-dispersed FeSe2 nanoparticles (FeSe2/Bi2Se3) for tetra-modal image-guided combined photothermal and radiation tumor therapy. Interestingly, upon addition of Bi(NO3)3, pre-made FeSe2 nanoparticles via cation exchange would be gradually converted into Bi2Se3 nanosheets, on which remaining FeSe2 nanoparticles are decorated. The yielded FeSe2/Bi2Se3 composite-nanostructures are then modified with polyethylene glycol (PEG). Taking advantages of the high r2 relaxivity of FeSe2, the X-ray attenuation ability of Bi2Se3, the strong near-infrared optical absorbance of the whole nanostructure, as well as the chelate-free radiolabeling of 64Cu on FeSe2/Bi2Se3-PEG, in vivo magnetic resonance/computer tomography/photoacoustic/position emission tomography multimodal imaging is carried out, revealing efficient tumor homing of FeSe2/Bi2Se3-PEG after intravenous injection. Utilizing the intrinsic physical properties of FeSe2/Bi2Se3-PEG, in vivo photothermal and radiation therapy to achieve synergistic tumor destruction is then realized, without causing obvious toxicity to the treated animals. This work presents a unique method to synthesize composite-nanostructures with highly integrated functionalities, promising not only for nano-biomedicine but also potentially for other different nanotechnology fields. [ABSTRACT FROM AUTHOR]

Up to date, a large variety of liposomal nanodrugs have been explored for cancer nanomedicine, showing encouraging results in both preclinical animal experiments and clinical treatment of cancer patients. Herein, a phospholipid conjugated with a cisplatin prodrug is used as the major structure component of liposomes together with other commercial lipids via self-assembling. By doping with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR), a lipophilic dye with strong near infrared (NIR) absorbance and fluorescence, the obtained DiR-Pt(IV)-liposome is found to be an effective probe for in vivo NIR fluorescence and photoacoustic bimodal imaging. Attributing to its intrinsically doped cis-Pt(IV) prodrug, efficient photothermal conversion ability, and excellent tumor homing ability, DiR-Pt(IV)-liposome confers greatly enhanced therapeutic outcomes in the combined photothermal-chemotherapy. Moreover, Pt(IV)-liposome is also demonstrated to be an efficient carrier for both small hydrophilic molecules and proteins, which are encapsulated inside the water-cavity of liposomes, further demonstrating the versatile functions of this nanoplatform. This study develops a unique type of liposomal nanomedicine with a prodrug conjugated phospholipid as the major structure component. Such Pt(IV)-liposome is featured with advantages including precisely defined/easily tunable drug compositions, stealth-like pharmacokinetics, efficient tumor passive uptake, and the capabilities to simultaneously load with various types of imaging or therapeutic agents. [ABSTRACT FROM AUTHOR]

Molybdenum oxide (MoOx) nanosheets with high near-infrared (NIR) absorbance and pH-dependent oxidative degradation properties were synthesized, functionalized with polyethylene glycol (PEG), and then used as a degradable photothermal agent and drug carrier. The nanosheets, which are relatively stable under acidic pH, could be degraded at physiological pH. Therefore, MoOx-PEG distributed in organs upon intravenous injection would be rapidly degraded and excreted without apparent in vivo toxicity. MoOx-PEG shows efficient accumulation in tumors, the acidic pH of which then leads to longer tumor retention of those nanosheets. Along with the capability of acting as a photothermal agent for effective tumor ablation, MoOx-PEG can load therapeutic molecules with high efficiencies. This concept of inorganic theranostic nanoagent should be relatively stable in tumors to allow imaging and treatment, while being readily degradable in normal organs to enable rapid excretion and avoid long-term retention/toxicity. [ABSTRACT FROM AUTHOR]

The poly(maleic anhydride-alt-1-octadecene-poly(ethylene glycol)) (C18PMH-PEG) modified single-walled carbon nanohorns (SWNHs) are designed with high stability and biocompatibility. The as-prepared SWNHs/C18PMH-PEG not only can serve as an excellent photothermal agent but also can be used as a promising photoacoustic imaging (PAI) agent both in vitro and in vivo due to its strong absorption in the near infrared (NIR) region. The PAI result reveals that the SWNHs/C18PMH-PEG possesses ultra long blood circulation time and can significantly be accumulated at the tumor site through the enhanced penetration and retention (EPR) effect. The maximum accumulation of SWNHs/C18PMH-PEG at tumor site could be achieved at the time point of 24 h after intravenous injection, which is considered to be the optimal time for the 808 nm laser treatment. The subsequent photothermal ablation of tumors can be achieved without triggering any side effects. Therefore, a PAI guided PTT platform based on SWNHs is proposed and highlights the potential theranostic application for biomedical uses. [ABSTRACT FROM AUTHOR]

Schematic illustration showed endogenously responsive intelligent nanoplatforms (acidic pH, H 2 O 2 , enzymes, GSH, hypoxia, vessel, and dual/multiple-responsive) for cancer theranostics. • This review summarizes the recent significant progress in intelligent nanoplatforms for TME-triggered cancer theranostics. • The methods for constructing these smart nanoplatforms based on the characteristic factors in the TME are discussed. • The limitations and prospects of these intelligent nanoplatforms for enhanced cancer therapy are also discussed. The design and development of tumor microenvironment (TME)-responsive intelligent nanoplatforms have attracted increasing interest to enhance the therapeutic effects of drugs, due to their potential to address some significant therapeutic issues, such as unsatisfying therapeutic outcomes and serious side effects. In this review, we mainly summarize the strategies used to construct these nanoplatforms based on characteristic factors present at high levels in the TME, including acidic pH values, endogenous H 2 O 2 , over-expressed enzymes, hypoxia-induced by insufficient oxygen supply, excess level of GSH, and other factors. These nanoplatforms that utilize the enhanced permeability and retention (EPR) effect and TME-triggered drug delivery enhance the therapeutic outcomes, minimize the side effects, and achieve image-guided therapy. Furthermore, the limitations and prospects of these nanoplatforms for enhanced cancer therapy are also discussed. [ABSTRACT FROM AUTHOR]

The abnormal tumor microenvironment (TME) featured with hypoxia, acidosis, dense extracellular matrix and increased tumor interstitial fluid pressure is closely related with the resistance of tumors to various therapies. Herein, a unique type of biocompatible nanoscale delivery system is fabricated by utilizing a chemotherapeutic drug, paclitaxel (PTX), to induce co-assembly of catalase and human serum albumin (HSA), the latter of which is pre-modified with chlorine e6 (Ce6), forming smart multifunctional HSA-Ce6-Cat–PTX nanoparticles via a rather simple one-step method. Upon intravenous injection, HSA-Ce6-Cat–PTX nanoparticles show high tumor accumulation and efficient intra-tumoral diffusion, likely owning to their changeable sizes that can maintain large initial sizes (~ 100 nm) during blood circulation and transform into small protein-drug complexes (< 20 nm) within the tumor. Meanwhile, catalase within those nanoparticles could trigger decomposition of endogenic TME H 2 O 2 to generate oxygen in-situ so as to relieve tumor hypoxia. This effect together with PTX-induced intra-tumoral perfusion enhancement is able to dramatically modulate TME to favor the anti-tumor effect in the combined photodynamic/chemotherapy with HSA-Ce6-Cat–PTX. Thus, our work presents a simple drug-induced self-assembly strategy to fabricate enzyme-loaded therapeutic albumin nanoparticles for synergistic cancer combination therapy. [ABSTRACT FROM AUTHOR]

Physical stimulus-responsive therapies often employing multifunctional theranostic agents responsive to external physical stimuli such as light, magnetic field, ultra-sound, radiofrequency, X-ray, etc., have been widely explored as novel cancer therapy strategies, showing encouraging results in many pre-clinical animal experiments. Unlike conventional cancer chemotherapy which often accompanies with severe toxic side effects, physical stimulus-responsive agents usually are non-toxic by themselves and would destruct cancer cells only under specific external stimuli, and thus could offer greatly reduced toxicity and enhanced treatment specificity. In addition, physical stimulus-responsive therapies can also be combined with other traditional therapeutics to achieve synergistic anti-tumor effects via a variety of mechanisms. In this review, we will summarize the latest progress in the development of physical stimulus-responsive therapies, and discuss the important roles of nanoscale theranostic agents involved in those non-conventional therapeutic strategies. [ABSTRACT FROM AUTHOR]

Theranostic agents with both imaging and therapeutic functions have attracted enormous interests in cancer diagnosis and treatment in recent years. In this work, we develop a novel theranostic agent based on Prussian blue nanocubes (PB NCs), a clinically approved agent with strong near-infrared (NIR) absorbance and intrinsic paramagnetic property, for in vivo bimodal imaging-guided photothermal therapy. After being coated with polyethylene glycol (PEG), the obtained PB-PEG NCs are highly stable in various physiological solutions. In vivo T 1 -weighted magnetic resonance (MR) and photoacoustic tomography (PAT) bimodal imaging uncover that PB-PEG NCs after intravenous (i.v.) injection show high uptake in the tumor. Utilizing the strong and super stable NIR absorbance of PB, in vivo cancer treatment is then conducted upon i.v. injection of PB-PEG NCs followed by NIR laser irradiation of the tumors, achieving excellent therapeutic efficacy in a mouse tumor model. Comprehensive blood tests and careful histological examinations reveal no apparent toxicity of PB-PEG NCs to mice at our tested dose, which is two-fold of the imaging/therapy dose, within two months. Our work highlights the great promise of Prussian blue with well engineered surface coating as a multifunctional nanoprobe for imaging-guided cancer therapy. [ABSTRACT FROM AUTHOR]

A large variety of cancers are associated with a high incidence of lymph node metastasis, which leads to a high risk of cancer death. Herein, we demonstrate that multimodal imaging guided photothermal therapy can inhibit tumor metastasis after surgery by burning the sentinel lymph nodes (SLNs) with metastatic tumor cells. A near-infrared dye, IR825, is absorbed onto human serum albumin (HSA), which is covalently linked with diethylenetriamine pentaacetic acid (DTPA) molecules to chelate gadolinium. The formed HSA-Gd-IR825 nanocomplex exhibits strong fluorescence together with high near-infrared (NIR) absorbance, and in the mean time could serve as a T1 contrast agent in magnetic resonance (MR) imaging. In vivo bi-modal fluorescence and MR imaging uncovers that HSA-Gd-IR825 after being injected into the primary tumor would quickly migrate into tumor-associated SLNs through lymphatic circulation. Utilizing the strong NIR absorbance of HSA-Gd-IR825, SLNs with metastatic cancer cells can be effectively ablated under exposure to a NIR laser. Such treatment when combined with surgery to remove the primary tumor offers remarkable therapeutic outcomes in greatly inhibiting further metastatic spread of cancer cells and prolonging animal survival. Our work presents an albumin-based theranostic nano-probe with functions of multimodal imaging and photothermal therapy, together with a ‘photothermal ablation assisted surgery’ strategy, promising for future clinical cancer treatment. [ABSTRACT FROM AUTHOR]