Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO₂) nanoparticles toward endogenous hydrogen peroxide (H₂O₂) within the tumor microenvironment to generate O₂, multifunctional chlorine e6 (Ce6) loaded MnO₂ nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO₂-PEG) are formulated to achieve enhanced tumor-specific PDT. In vitro studies under an oxygen-deficient atmosphere uncover that Ce6@MnO₂-PEG nanoparticles could effectively enhance the efficacy of light-induced PDT due to the increased intracellular O₂ level benefited from the reaction between MnO₂ and H₂O₂, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO₂-PEG nanoparticles upon intravenous injection as revealed by T1-weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO₂-PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.

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.

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 r ₂ 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.

Smart drug delivery systems with on-demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light-responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on-demand light-triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)-sensitive bis-(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR-BATA-BSA-PEG, namely CMSNR-B-PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis-Pt (IV) pre-drug conjugated third generation dendrimer (G3-Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA-PEG from the nanorod surface and thus triggering release of loaded DOX or G3-Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR-B-PEG with either DOX or G3-Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on-demand release of therapeutics specifically in the tumor under light irradiation.

The development of cancer combination therapies, many of which rely on nanoscale theranostic agents, has received increasing attention in recent years. In this work, polyethylene glycol (PEG) modified mesoporous silica (MS) coated single-walled carbon nanotubes (SWNTs) are fabricated and utilized as a multifunctional platform for imaging guided combination therapy of cancer. A model chemotherapy drug, doxorubicin (DOX), could be loaded into the mesoporous structure of the obtained SWNT@MS-PEG nano-carriers with high efficiency. Upon stimulation under near-infrared (NIR) light, photothermally triggered drug release from DOX loaded SWNT@MS-PEG is observed inside cells, resulting in a synergistic cancer cell killing effect. As revealed by both photoacoustic (PA) and magnetic resonance (MR) imaging, we further uncover efficient tumor accumulation of SWNT@MS-PEG/DOX after intravenous injection into mice. In vivo combination therapy using this agent is further demonstrated in a mouse tumor model, achieving a remarkable synergistic anti-tumor effect superior to that obtained by mono-therapy. Our work presents a new type of theranostic nano-platform, which could load therapeutic molecules with high efficiency, be responsive to external NIR stimulation, and at the same time serve as a diagnostic imaging agent.

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus-responsive, RBC-based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near-infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light-induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC-based cancer cell targeted drug delivery and light-controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.

Combining different therapeutic strategies to treat cancer by overcoming limitations of conventional cancer therapies has shown great promise in both fundamental and clinical studies. Herein, by adding ¹³¹I when making iodine-doped CuS nanoparticles, CuS/[¹³¹I]I nanoparticles are obtained, which after functionalization with polyethylene glycol (PEG) are used for radiotherapy (RT) and photothermal therapy (PTT), by utilizing their intrinsic high near-infrared absorbance and the doped ¹³¹I-radioactivity, respectively. The combined RT and PTT based on CuS/[¹³¹I]I-PEG is then conducted, achieving remarkable synergistic therapeutic effects as demonstrated in the treatment of subcutaneous tumors. In the meanwhile, as revealed by bimodal nuclear imaging and computed tomography (CT) imaging, it is found that CuS/[¹³¹I]I-PEG nanoparticles after being injected into primary solid tumors could migrate to and retain in their nearby sentinel lymph nodes. Importantly, the combined RT and PTT applied on those lymph nodes to assist surgical resection of primary tumors results in remarkably inhibited cancer metastasis and greatly prolonged animal survival. In vivo toxicology studies further reveal that our CuS/I-PEG is not obviously toxic to animals at fourfold of the treatment dose. This work thus demonstrates the potential of combining RT and PTT using a single nanoagent for imaging-guided treatment of metastatic tumors.

Development of biodegradable nanomaterials for drug delivery and cancer theranostics has attracted great attention in recent years. In this work, polydopamine (PDA), a biocompatible polymer, is developed as a promising carrier for loading of both radionuclides and an anticancer drug to realize nuclear-imaging-guided combined radioisotope therapy (RIT) and chemotherapy of cancer in one system. It is found that PDA nanoparticles after modification with poly(ethylene glycol) (PEG) can successfully load several different radionuclides such as ^99mTc and ¹³¹I, as well as an anticancer drug doxorubicin (DOX). While labeling PDA-PEG with ^99mTc (^99mTc-PDA-PEG) enables in vivo single photon emission computed tomography imaging, nanoparticles co-loaded with ¹³¹I and DOX (¹³¹I-PDA-PEG/DOX) can be utilized for combined RIT and chemotherapy, which offers effective cancer treatment efficacy in a remarkably synergistic manner, without rendering significant toxicity to the treated animals. Therefore, this study presents an interesting class of biocompatible nanocarriers, which allow the combination of RIT and chemotherapy, the two extensively applied cancer therapeutic strategies, promising for future clinic translations in cancer treatment.

The booming development of nanomedicine offers great opportunities for cancer diagnostics and therapeutics. Herein, a magnetic targeting-enhanced cancer theranostic strategy using a multifunctional magnetic-plasmonic nano-agent is developed, and a highly effective in vivo tumor photothermal therapy, which is carefully planed based on magnetic resonance (MR)/photoacoustic (PA) multimodal imaging, is realized. By applying an external magnetic field (MF) focused on the targeted tumor, a magnetic targeting mediated enhanced permeability and retention (MT-EPR) effect is observed. While MR scanning provides tumor localization and reveals time-dependent tumor homing of nanoparticles for therapeutic planning, photoacoustic imaging with higher spatial resolution allows noninvasive fine tumor margin delineation and vivid visualization of three dimensional distributions of theranostic nanoparticles inside the tumor. Utilizing the near-infrared (NIR) plasmonic absorbance of those nanoparticles, selective photothermal tumor ablation, whose efficacy is predicted by real-time infrared thermal imaging intra-therapeutically, is carried out and then monitored by MR imaging for post-treatment prognosis. Overall, this study illustrates the concept of imaging-guided MF-targeted photothermal therapy based on a multifunctional nano-agent, aiming at optimizing therapeutic planning to achieve the most efficient cancer therapy.

The integration of diagnostic and therapeutic functionalities on a single theranostic nano-system holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Herein, a multifunctional polymeric nano-micelle system that contains a photosensitizer chlorin e6 (Ce6) is successfully fabricated, at the same time serving as a chelating agent for Gd³⁺, together with a near-infrared (NIR) dye, IR825. With a r₁ relativity 7 times higher than that of the commercial agent Magnevist, strong fluorescence offered by Ce6, and high NIR absorbance attributed to IR825, these theranostic micelles can be utilized as a contrast agent for triple modal magnetic resonance (MR), fluorescence, and photoacoustic imaging of tumors in a mouse model. The combined photothermal and photodynamic therapy is then carried out, achieving a synergistic anti-tumor effect both in vitro and in vivo. Different from single photo treatment modalities which only affect the superficial region of the tumor under mild doses, the combination therapy at the same dose using this agent is able to induce significant damage to both superficial and deep parts of the tumor. Therefore, this work presents a polymer based theranostic platform with great potential in multimodal imaging and combination therapy of cancer.

Recently, near-infrared (NIR) absorbing conjugated polymeric nanoparticles have received significant attention in photothermal therapy of cancer. Herein, polypyrrole (PPy), a NIR-absorbing conjugate polymer, is used to coat ultra-small iron oxide nanoparticles (IONPs), obtaining multifunctional IONP@PPy nanocomposite which is further modified by the biocompatible polyethylene glycol (PEG) through a layer-by-layer method to acquire high stability in physiological solutions. Utilizing the optical and magnetic properties of the yielded IONP@PPy-PEG nanoparticles, in vivo magnetic resonance (MR) and photoacoustic imaging of tumor-bearing mice are conducted, revealing strong tumor uptake of those nanoparticles after intravenous injection. In vivo photothermal therapy is then designed and carried out, achieving excellent tumor ablation therapeutic effect in mice experiments. These results promise the use of multifunctional NIR-absorbing organic-inorganic hybrid nanomaterials, such as IONP@PPy-PEG presented here, for potential applications in cancer theranostics.

A pH-responsive nanocarrier is developed by coating nanoscale graphene oxide (NGO) with dual types of polymers, polyethylene glycol (PEG) and poly(allylamine hydrochloride) (PAH), the latter of which is then modified with 2,3-dimethylmaleic anhydride (DA) to acquire pH-dependent charge reversibility. After loading with doxorubicin (DOX), a chemotherapy drug, the obtained NGO-PEG-DA/DOX complex exhibits a dual pH-responsiveness, showing markedly enhanced cellular uptake under the tumor microenvironmental pH, and accelerated DOX release under a further lowered pH inside cell lysosomes. Combining such a unique behavior with subsequently slow efflux of DOX, NGO-PEG-DA/DOX offers remarkably improved cell killing for drug-resistant cancer cells under the tumor microenvironmental pH in comparison with free DOX. Exploiting its excellent photothermal conversion ability, combined chemo- and photothermal therapy is further demonstrated using NGO-PEG-DA/DOX, realizing a synergistic therapeutic effect. This work presents a novel design of surface chemistry on NGO for the development of smart drug delivery systems responding to the tumor microenvironment and external physical stimulus, with the potential to overcome drug resistance.

Much has been done to search for highly efficient and inexpensive electrocatalysts for the hydrogen evolution reaction (HER), which is critical to a range of electrochemical and photoelectrochemical processes. A new, high-temperature solution-phase method for the synthesis of ultrathin WS₂ nanoflakes is now reported. The resulting product possesses monolayer thickness with dimensions in the nanometer range and abundant edges. These favorable structural features render the WS₂ nanoflakes highly active and durable catalysts for the HER in acids. The catalyst exhibits a small HER overpotential of approximately 100 mV and a Tafel slope of 48 mV/decade. These ultrathin WS₂ nanoflakes represent an attractive alternative to the precious platinum benchmark catalyst and rival MoS₂ materials that have recently been heavily scrutinized for the electrocatalytic HER.

Much has been done to search for highly efficient and inexpensive electrocatalysts for the hydrogen evolution reaction (HER), which is critical to a range of electrochemical and photoelectrochemical processes. A new, high-temperature solution-phase method for the synthesis of ultrathin WS₂ nanoflakes is now reported. The resulting product possesses monolayer thickness with dimensions in the nanometer range and abundant edges. These favorable structural features render the WS₂ nanoflakes highly active and durable catalysts for the HER in acids. The catalyst exhibits a small HER overpotential of approximately 100 mV and a Tafel slope of 48 mV/decade. These ultrathin WS₂ nanoflakes represent an attractive alternative to the precious platinum benchmark catalyst and rival MoS₂ materials that have recently been heavily scrutinized for the electrocatalytic HER.

Stem cells have generated a great deal of excitement in cell-based therapies. Here, a unique class of multifunctional nanoparticles (MFNPs) with both upconversion luminescence (UCL) and superparamagnetic properties is used for stem cell research. It is discovered that after being labeled with MFNPs, mouse mesenchymal stem cells (mMSCs) are able to maintain their viability and differentiation ability. In vivo UCL imaging of MFNP-labeled mMSCs transplanted into animals is carried out, achieving ultrahigh tracking sensitivity with a detection limit as low as ≈10 cells in a mouse. Using both UCL optical and magnetic resonance (MR) imaging approaches, MFNP-labeled mMSCs are tracked after being intraperitoneally injected into wound-bearing mice under a magnetic field. The translocation of mMSCs from the injection site to the wound nearby the magnet is observed and, intriguingly, a remarkably improved tissue repair effect is observed as the result of magnetically induced accumulation of stem cells in the wound site. The results demonstrate the use MFNPs as novel multifunctional probes for labeling, in vivo tracking, and manipulation of stem cells, which is promising for imaging guided cell therapies and tissue engineering.

Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue-penetrating near-infrared light (NIR) light. Herein, we synthesize manganese (Mn²⁺)-doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (¹O₂) to kill cancer cells. A layer-by-layer (LbL) self-assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading (UCNP@2xCe6) are found to be optimal in terms of Ce6 loading and ¹O₂ generation. By further coating UCNP@2xCe6 with an outer layer of charge-reversible polymer containing dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a UCNP@2xCe6-DMMA-PEG nanocomplex, the surface of which is negatively charged and PEG coated under pH 7.4; this could be converted to have a positively charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR-induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn²⁺-doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of UCNP@2xCe6-DMMA-PEG inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge-reversible UCNP@2xCe6-DMMA-PEG nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor-homing of these pH-responsive charge-switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic intravenous injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH-responsive PDT agents promising in cancer theranostics.

Poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) nanoparticles, after being coated with polyethylene glycol (PEG), are used as a drug carrier to load various types of aromatic therapeutic molecules, including chemotherapy drugs doxorubicin (DOX) and SN38, as well as a photodynamic agent chlorin e6 (Ce6), through π–π stacking and hydrophobic interaction. Interesting functionalities of PEDOT:PSS-PEG as an unique versatile drug delivery platform are discovered. Firstly, for water-insoluble drugs such as SN38, the loading on PEDOT:PSS-PEG dramatically enhances its water solubility, while maintaining its cytotoxicity to cancer cells. Secondly, the delivery of Ce6 by PEDOT:PSS-PEG is able to remarkably accelerate the cellular uptake of Ce6 molecules, and thus offers improved photodynamic therapeutic efficacy. Using DOX-loaded PEDOT:PSS-PEG as the model system, it is demonstrated that the photothermal effect of PEDOT:PSS-PEG can be utilized to promote the delivery of this chemotherapeutic agent, achieving a combined photothermal- and chemotherapy with an obvious synergistic cancer killing effect. Moreover, it is also shown that multiple types of therapeutic agents could be simultaneously loaded on PEDOT:PSS-PEG nanoparticles and delivered into cancer cells. This work highlights the great potential of NIR-absorbing polymeric nanoparticles as multifunctional drug carriers for potential cancer combination therapy with high efficacy.

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near-infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra-high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low-power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR-absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.

Stem cells have shown great potential in regenerative medicine and attracted tremendous interests in recent years. Sensitive and reliable methods for stem cell labeling and in vivo tracking are thus urgently needed. Here, a novel approach to label human mesenchymal stem cells (hMSCs) with single-walled carbon nanotubes (SWNTs) for in vivo tracking by triple-modal imaging is presented. It is shown that polyethylene glycol (PEG) functionalized SWNTs conjugated with protamine (SWNT-PEG-PRO) exhibit extremely efficient cell entry into hMSCs, without affecting their proliferation and differentiation. The strong inherent resonance Raman scattering of SWNTs is used for in vitro and in vivo Raman imaging of SWNT-PEG-PRO-labeled hMSCs, enabling ultrasensitive in vivo detection of as few as 500 stem cells administrated into mice. On the other hand, the metallic catalyst nanoparticles attached on nanotubes can be utilized as the T2-contrast agent in magnetic resonance (MR) imaging of SWNT-labeled hMSCs. Moreover, in vivo photoacoustic imaging of hMSCs in mice is also demonstrated. The work reveals that SWNTs with appropriate surface functionalization have the potential to serve as multifunctional nanoprobes for stem cell labeling and multi-modal in vivo tracking.