Engineering 2D Mesoporous Silica@MXene‐Integrated 3D‐Printing Scaffolds for Combinatory Osteosarcoma Therapy and NO‐Augmented Bone Regeneration

The rising concerns of the recurrence and bone deficiency in surgical treatment of malignant bone tumors have raised an urgent need of the advance of multifunctional therapeutic platforms for efficient tumor therapy and bone regeneration. Herein, the construction of a multifunctional biomaterial system is reported by the integration of 2D Nb₂C MXene wrapped with S‐nitrosothiol (R? SNO)‐grafted mesoporous silica with 3D‐printing bioactive glass (BG) scaffolds (MBS). The near infrared (NIR)‐triggered photonic hyperthermia of MXene in the NIR‐II biowindow and precisely controlled nitric oxide (NO) release are coordinated for multitarget ablation of bone tumors to enhance localized osteosarcoma treatment. The in situ formed phosphorus and calcium components degraded from BG scaffold promote bone‐regeneration bioactivity, augmented by sufficient blood supply triggered by on‐demand NO release. The tunable NO generation plays a crucial role in sequential adjuvant tumor ablation, combinatory promotion of coupled vascularization, and bone regeneration. This study demonstrates a combinatory osteosarcoma ablation and a full osseous regeneration as enabled by the implantation of MBS. The design of multifunctional scaffolds with the specific features of controllable NO release, highly efficient photothermal conversion, and stimulatory bone regeneration provides an intriguing biomaterial platform for the diversified treatment of bone tumors.     

Trifolium‐like Platinum Nanoparticle‐Mediated Photothermal Therapy Inhibits Tumor Growth and Osteolysis in a Bone Metastasis Model

Bone metastasis is a frequent and fatal complication of cancer that lacks effective clinical treatment. Photothermal therapy represents a new strategy for the destruction of multiple cancers. In this study, trifolium‐like platinum nanoparticles (TPNs) with small size and excellent photothermal conversion property are prepared via a facile and green method. TPNs show minimal cytotoxicity on normal cell lines and kill cancer cells upon exposure to a near‐infrared light. These nanoparticles effectively inhibit tumor growth and prevent osteolysis in a bone metastasis model. This study offers a promising strategy in the treatment of bone metastasis.     

A Tumor‐Microenvironment‐Activated Nanozyme‐Mediated Theranostic Nanoreactor for Imaging‐Guided Combined Tumor Therapy

Activatable theranostic agents that can be activated by tumor microenvironment possess higher specificity and sensitivity. Here, activatable nanozyme‐mediated 2,2′‐azino‐bis (3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) loaded ABTS@MIL‐100/poly(vinylpyrrolidine) (AMP) nanoreactors (NRs) are developed for imaging‐guided combined tumor therapy. The as‐constructed AMP NRs can be specifically activated by the tumor microenvironment through a nanozyme‐mediated “two‐step rocket‐launching‐like” process to turn on its photoacoustic imaging signal and photothermal therapy (PTT) function. In addition, simultaneously producing hydroxyl radicals in response to the high H₂O₂ level of the tumor microenvironment and disrupting intracellular glutathione (GSH) endows the AMP NRs with the ability of enhanced chemodynamic therapy (ECDT), thereby leading to more efficient therapeutic outcome in combination with tumor‐triggered PTT. More importantly, the H₂O₂‐activated and acid‐enhanced properties enable the AMP NRs to be specific to tumors, leaving the normal tissues unharmed. These remarkable features of AMP NRs may open a new avenue to explore nanozyme‐involved nanoreactors for intelligent, accurate, and noninvasive cancer theranostics.     

Programmable NIR‐II Photothermal‐Enhanced Starvation‐Primed Chemodynamic Therapy using Glucose Oxidase‐Functionalized Ancient Pigment Nanosheets

Chemodynamic therapy (CDT) has attracted considerable attention recently, but the poor reaction kinetics restrict its practical utility in clinic. Herein, glucose oxidase (GOx) functionalized ancient pigment nanosheets (SrCuSi₄O₁₀, SC) for programmable near‐infrared II (NIR‐II) photothermal‐enhanced starvation primed CDT is developed. The SC nanosheets (SC NSs) are readily exfoliated from SC bulk suspension in water and subsequently functionalized with GOx to form the nanocatalyst (denoted as SC@G NSs). Upon laser irradiation, the photothermal effect of SC NSs can enhance the catalytic activity of GOx for NIR‐II photothermal‐enhanced starvation therapy, which effectively eliminates intratumoral glucose and produces abundant hydrogen peroxide (H₂O₂). Importantly, the high photothermal‐conversion efficiency (46.3%) of SC@G NSs in second biological window permits photothermal therapy of deep‐seated tumors under the guidance of NIR‐II photoacoustic imaging. Moreover, the acidity amplification due to gluconic acid generation will in turn accelerate the degradation of SC NSs, facilitating the release of strontium (Sr) and copper (Cu) ions. Both the elevated H₂O₂ and the released ions will prime the Cu²⁺/Sr²⁺‐H₂O₂ reaction for enhanced CDT. Thus, a programmable NIR‐II photothermal‐enhanced starvation primed CDT is established to combat cancer with minimal side effects.     

Long‐Range Nanoparticle Surface‐Energy‐Transfer Ruler for Monitoring Photothermal Therapy Response

A recent gold nanotechnology‐driven approach opens up a new possibility for the destruction of cancer cells through photothermal therapy. Ultimately, photothermal therapy may enter into clinical therapy and, as a result, there is an urgent need for techniques to monitor the tumor response to therapy. Driven by this need, a nanoparticle surface‐energy‐transfer (NSET) approach to monitor the photothermal therapy process by measuring a simple fluorescence intensity change is reported. The fluorescence intensity change is due to the light‐controlled photothermal release of single‐stranded DNA/RNA via dehybridization during the therapy process. Time‐dependent results show that just by measuring the fluorescence intensity change, the photothermal therapy response during the therapy process can be monitored. The possible mechanism and operating principle of the NSET assay are discussed. Ultimately, this NSET assay could have enormous potential applications in rapid, on‐site monitoring of the photothermal therapy process, which is critical to providing effective treatment of cancer and multidrug‐resistant bacterial infections.     

A Spontaneous 3D Bone‐On‐a‐Chip for Bone Metastasis Study of Breast Cancer Cells

Bone metastasis occurs at ≈70% frequency in metastatic breast cancer. The mechanisms used by tumors to hijack the skeleton, promote bone metastases, and confer therapeutic resistance are poorly understood. This has led to the development of various bone models to investigate the interactions between cancer cells and host bone marrow cells and related physiological changes. However, it is challenging to perform bone studies due to the difficulty in periodic sampling. Herein, a bone‐on‐a‐chip (BC) is reported for spontaneous growth of a 3D, mineralized, collagenous bone tissue. Mature osteoblastic tissue of up to 85 µm thickness containing heavily mineralized collagen fibers naturally formed in 720 h without the aid of differentiation agents. Moreover, co‐culture of metastatic breast cancer cells is examined with osteoblastic tissues. The new bone‐on‐a‐chip design not only increases experimental throughput by miniaturization, but also maximizes the chances of cancer cell interaction with bone matrix of a concentrated surface area and facilitates easy, frequent observation. As a result, unique hallmarks of breast cancer bone colonization, previously confirmed only in vivo, are observed. The spontaneous 3D BC keeps the promise as a physiologically relevant model for the in vitro study of breast cancer bone metastasis.     

Rapid Biofilm Eradication on Bone Implants Using Red Phosphorus and Near‐Infrared Light

Bone‐implant‐associated infections are common after orthopedic surgery due to impaired host immune response around the implants. In particular, when a biofilm develops, the immune system and antibiotic treatment find it difficult to eradicate, which sometimes requires a second operation to replace the infected implants. Most strategies have been designed to prevent biofilms from forming on the surface of bone implants, but these strategies cannot eliminate the biofilm when it has been established in vivo. To address this issue, a nonsurgical, noninvasive treatment for biofilm infection must be developed. Herein, a red‐phosphorus–IR780–arginine–glycine–aspartic‐acid–cysteine coating on titanium bone implants is prepared. The red phosphorus has great biocompatibility and exhibits efficient photothermal ability. The temperature sensitivity of Staphylococcus aureus biofilm is enhanced in the presence of singlet oxygen (¹O₂) produced by IR780. Without damaging the normal tissue, the biofilm can be eradicated through a safe near‐infrared (808 nm) photothermal therapy at 50 °C in vitro and in vivo. This approach reaches an antibacterial efficiency of 96.2% in vivo with 10 min of irradiation at 50 °C. Meanwhile, arginine–glycine–aspartic‐acid–cysteine decorated on the surface of the implant can improve the cell adhesion, proliferation, and osteogenic differentiation.     

Molecular Targeting‐Mediated Mild‐Temperature Photothermal Therapy with a Smart Albumin‐Based Nanodrug

Photothermal therapy (PTT) usually requires hyperthermia >50 °C for effective tumor ablation, which inevitably induces heating damage to the surrounding normal tissues/organs. Moreover, low tumor retention and high liver accumulation are the two main obstacles that significantly limit the efficacy and safety of many nanomedicines. To solve these problems, a smart albumin‐based tumor microenvironment‐responsive nanoagent is designed via the self‐assembly of human serum albumin (HSA), dc‐IR825 (a cyanine dye and a photothermal agent), and gambogic acid (GA, a heat shock protein 90 (HSP90) inhibitor and an anticancer agent) to realize molecular targeting‐mediated mild‐temperature PTT. The formed HSA/dc‐IR825/GA nanoparticles (NPs) can escape from mitochondria to the cytosol through mitochondrial disruption under near‐infrared (NIR) laser irradiation. Moreover, the GA molecules block the hyperthermia‐induced overexpression of HSP90, achieving the reduced thermoresistance of tumor cells and effective PTT at a mild temperature (<45 °C). Furthermore, HSA/dc‐IR825/GA NPs show pH‐responsive charge reversal, effective tumor accumulation, and negligible liver deposition, ultimately facilitating synergistic mild‐temperature PTT and chemotherapy. Taken together, the NIR‐activated NPs allow the release of molecular drugs more precisely, ablate tumors more effectively, and inhibit cancer metastasis more persistently, which will advance the development of novel mild‐temperature PTT‐based combination strategies.     

Near‐Infrared‐Light‐Activatable Nanomaterial‐Mediated Phototheranostic Nanomedicines: An Emerging Paradigm for Cancer Treatment

Cancer is one of the most deadly diseases threatening the lives of humans. Although many treatment methods have been developed to tackle cancer, each modality of cancer treatment has its own limitations and drawbacks. The development of minimally invasive treatment modalities for cancers remains a great challenge. Near‐infrared (NIR) light‐activated nanomaterial‐mediated phototherapies, including photothermal and photodynamic therapies, provide an alternative means for spatially and temporally controlled minimally invasive treatments of cancers. Nanomaterials can serve as nanocargoes for the delivery of chemo‐drugs, diagnostic contrast reagents, and organic photosensitizers, and can be used to directly generate heat or reactive oxygen species for the treatment of tumors without the need for organic photosensitizers with NIR‐light irradiation. Here, current progress in NIR‐light‐activated nanomaterial‐mediated photothermal therapy and photodynamic therapy is summarized. Furthermore, the effects of size, shape, and surface functionalities of nanomaterials on intracellular uptake, macrophage clearance, biodistribution, cytotoxicities, and biomedical efficacies are discussed. The use of various types of nanomaterials, such as gold nanoparticles, carbon nanotubes, graphene, and many other inorganic nanostructures, in combination with diagnostic and therapeutic modalities for solid tumors, is briefly reviewed.     

Self‐Assembled Peptide‐ and Protein‐Based Nanomaterials for Antitumor Photodynamic and Photothermal Therapy

Tremendous interest in self‐assembly of peptides and proteins towards functional nanomaterials has been inspired by naturally evolving self‐assembly in biological construction of multiple and sophisticated protein architectures in organisms. Self‐assembled peptide and protein nanoarchitectures are excellent promising candidates for facilitating biomedical applications due to their advantages of structural, mechanical, and functional diversity and high biocompability and biodegradability. Here, this review focuses on the self‐assembly of peptides and proteins for fabrication of phototherapeutic nanomaterials for antitumor photodynamic and photothermal therapy, with emphasis on building blocks, non‐covalent interactions, strategies, and the nanoarchitectures of self‐assembly. The exciting antitumor activities achieved by these phototherapeutic nanomaterials are also discussed in‐depth, along with the relationships between their specific nanoarchitectures and their unique properties, providing an increased understanding of the role of peptide and protein self‐assembly in improving the efficiency of photodynamic and photothermal therapy.     

Photoconversion‐Tunable Fluorophore Vesicles for Wavelength‐Dependent Photoinduced Cancer Therapy

Photoconversion tunability of fluorophore dye is of great interest in cancer nanomedicine such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, this paper reports wavelength‐dependent photoconversional polymeric vesicles of boron dipyrromethene (Bodipy) fluorophore for either PDT under 660 nm irradiation or PTT under 785 nm irradiation. After being assembled within polymeric vesicles at a high drug loading, Bodipy molecules aggregate in the conformations of both J‐type and H‐type, thereby causing red‐shifted absorption into near‐infrared region, ultralow radiative transition, and ideal resistance to photobleaching. Such vesicles further possess enhanced blood circulation, preferable tumor accumulation, as well as superior cell uptake as compared to free Bodipy. In particular, the vesicles mainly generate abundant intracellular singlet oxygen for PDT treatment under 660 nm irradiation, while they primarily produce a potent hyperthermia for PTT with tumor ablation through singlet oxygen‐synergized photothermal necrosis under 785 nm irradiation. This approach provides a facile and general strategy to tune photoconversion characteristics of fluorophore dyes for wavelength‐dependent photoinduced cancer therapy.     

Mesoporous‐Silica‐Coated Up‐Conversion Fluorescent Nanoparticles for Photodynamic Therapy

Near‐infrared (NIR)‐to‐visible up‐conversion fluorescent nanoparticles have potential to be used for photodynamic therapy (PDT) in deep tissue because NIR light can penetrate thick tissue due to weak absorption in the optical window. Here a uniform layer of mesoporous silica is coated onto NaYF₄ up‐converting nanocrystals, with a large surface area of ≈770 m² g^?1 and an average pore size of 2 nm. A photosensitizer, zinc phthalocyanine, is incorporated into the mesoporous silica. Upon excitation by a NIR laser, the nanocrystals convert NIR light to visible light, which further activates the photosensitizer to release reactive singlet oxygen to kill cancer cells. The photosensitizer encapsulated in mesoporous silica is protected from degradation in the harsh biological environment. It is demonstrated that the photosensitizers loaded into the porous silica shell of the nanoparticles are not released out of the silica while they continuously produce singlet oxygen upon excitation by a NIR laser. The nanoparticles are reusable as the photosensitizers encapsulated in the silica are removed by soaking in ethanol.     

Bone‐specific alkaline phosphatase and bone turnover in African American hemodialysis patients

Introduction: Noninvasive measures of bone activity include intact parathyroid hormone (iPTH) and bone‐specific alkaline phosphatase (BSAP). Whether BSAP measurement alone or in combination with other biochemical data provides more reliable information about bone turnover than iPTH alone in African Americans on hemodialysis is unknown. Methods: This cross‐sectional study aimed to determine the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in classifying bone biopsy findings. Forty‐three African American hemodialysis patients were available for analysis. Biochemical data on the day of biopsy across a spectrum of qualitative histologic bone features were compared. Classification and regression tree analysis was used to determine both the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in identifying bone turnover status. Findings: Seven subjects had adynamic disease, 31 had mild/moderate hyperparathyroid bone features, and five had severe hyperparathyroid bone disease. BSAP was the optimal predictor of bone biopsy with a cutoff point of 22 ng/mL. Calcium and phosphorus had no predictive value. At BSAP ≤ 22 ng/mL, subjects had either adynamic bone disease or mild/moderate hyperparathyroid bone disease but iPTH was not useful in further classifying biopsy findings. When BSAP was >22 ng/mL, subjects had either mild/moderate or severe hyperparathyroid bone disease, and iPTH was useful in further classifying biopsy findings. With BSAP > 22 ng/mL and iPTH < 726 pg/mL, all subjects had mild/moderate bone turnover features. Discussion: Compared to iPTH, BSAP was shown to be the optimal predictor of biopsy findings with an optimal cutoff at 22 ng/mL.     

Rhenium‐188 Labeled Tungsten Disulfide Nanoflakes for Self‐Sensitized,Near‐Infrared Enhanced Radioisotope Therapy

Radioisotope therapy (RIT), in which radioactive agents are administered or implanted into the body to irradiate tumors from the inside, is a clinically adopted cancer treatment method but still needs improvement to enhance its performances. Herein, it is found that polyethylene glycol (PEG) modified tungsten disulfide (WS₂) nanoflakes can be easily labeled by ¹⁸⁸Re, a widely used radioisotope for RIT, upon simple mixing. Like other high‐Z elements acting as radiosensitizers, tungsten in the obtained ¹⁸⁸Re‐WS₂‐PEG would be able to absorb ionization radiation generated from ¹⁸⁸Re, enabling ‘‘self‐sensitization’’ to enhance the efficacy of RIT as demonstrated in carefully designed in vitro experiments of this study. In the meanwhile, the strong NIR absorbance of WS₂‐PEG could be utilized for NIR light‐induced photothermal therapy (PTT), which if applied on tumors would be able to greatly relieve their hypoxia state and help to overcome hypoxia‐associated radioresistance of tumors. Therefore, with ¹⁸⁸Re‐WS₂‐PEG as a multifunctional agent, which shows efficient passive tumor homing after intravenous injection, in vivo self‐sensitized, NIR‐enhanced RIT cancer treatment is realized, achieving excellent tumor killing efficacy in a mouse tumor model. This work presents a new concept of applying nanotechnology in RIT, by delivering radioisotopes into tumors, self‐sensitizing the irradiation‐induced cell damage, and modulating the tumor hypoxia state to further enhance the therapeutic outcomes.     

Fluorescent Imaging‐Guided Chemotherapy‐and‐Photodynamic Dual Therapy with Nanoscale Porphyrin Metal–Organic Framework

Imaging‐guided therapy systems (IGTSs) are revolutionary techniques used in cancer treatment due to their safety and efficiency. IGTSs should have tunable compositions for bioimaging, a suitable size and shape for biotransfer, sufficient channels and/or pores for drug loading, and intrinsic biocompatibility. Here, a biocompatible nanoscale zirconium‐porphyrin metal–organic framework (NPMOF)‐based IGTS that is prepared using a microemulsion strategy and carefully tuned reaction conditions is reported. A high content of porphyrin (59.8%) allows the achievement of efficient fluorescent imaging and photodynamic therapy (PDT). The 1D channel of the Kagome topology of NPMOFs provides a 109% doxorubicin loading and pH‐response smart release for chemotherapy. The fluorescence guiding of the chemotherapy‐and‐PDT dual system is confirmed by the concentration of NPMOFs at cancer sites after irradiation with a laser and doxorubicin release, while low toxicity is observed in normal tissues. NPMOFs are established as a promising platform for the early diagnosis of cancer and initial therapy.     

Ultrastable Near‐Infrared Conjugated‐Polymer Nanoparticles for Dually Photoactive Tumor Inhibition

It is highly desired that satisfactory photoactive agents with ideal photophysical characteristics are explored for potent cancer phototherapeutics. Herein, bifunctional nanoparticles of low‐bandgap donor–acceptor (D–A)‐type conjugated‐polymer nanoparticles (CP‐NPs) are developed to afford a highly efficient singlet‐to‐triplet transition and photothermal conversion for near‐infrared (NIR) light‐induced photodynamic (PDT)/photothermal (PTT) treatment. CP‐NPs display remarkable NIR absorption with the peak at 782 nm, and perfect resistance to photobleaching. Photoexcited CP‐NPs undergo singlet‐to‐triplet intersystem crossing through charge transfer in the excited D–A system and simultaneous nonradiative decay from the electron‐deficient electron acceptor isoindigo derivative under single‐wavelength NIR light irradiation, leading to distinct singlet oxygen quantum yield and high photothermal conversion efficiency. Moreover, the CP‐NPs display effective cellular uptake and cytoplasmic translocation from lysosomes, as well as effective tumor accumulation, thus promoting severe light‐triggered damage caused by favorable reactive oxygen species (ROS) generation and potent hyperthermia. Thus, CP‐NPs achieve photoactive cell damage through their photoconversion ability for synergistic PDT/PTT treatment with tumor ablation. The proof‐of‐concept design of D–A‐type conjugated‐polymer nanoparticles with ideal photophysical characteristics provides a general approach to afford potent photoactive cancer therapy.