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Radiotherapy (RT), including external beam RT and internal radiation therapy, uses high-energy ionizing radiation to kill tumor cells. However, ionizing radiation inevitably damages the surrounding normal tissues. Therefore, it is imperative to develop precision RT for improving the treatment outcome and reducing the adverse effects. Recent breakthroughs in nanotechnology have provided a variety of strategies by which RT can precisely and efficiently eradicate local tumors. In this review, we would like to summarize a series of nanotechnology-mediated strategies to achieve precision RT, including tumor-targeted delivery, image-guided precision radiotherapy, and exo/endogenous stimuli-responsive nanomedicines for enhanced tumor accumulation/penetration. In addition, this review will also discuss two representative featured applications of precision RT: RT-induced immunotherapy against cancer metastasis and radioprotection of the surrounding healthy tissues. Since RT is usually thought to be only effective for treating local tumors, this review will interpret the unusual mechanisms of RT-mediated systemic antitumor immunity for eliminating distant cancer metastasis as well as the abscopal effects of RT in combination with other treatments (

End-effector type upper limb rehabilitation robots (ULRRs) are connected to patients at one distal point, making them have simple structures and less complex control algorithms, and they can avoid abnormal motion and posture of the target anatomical joints and specific muscles. Given that the end-effector type ULRR focuses more on the rehabilitation of the combined motion of upper limb chain, assisting the patient to perform collaborative tasks, and its intervention has some advantages than the exoskeleton type ULRR, we developed a novel three-degree-of-freedom (DOF) end-effector type ULRR. The advantage of the mechanical design is that the designed end-effector type ULRR can achieve three DOFs by using a four-bar mechanism and a lifting mechanism; we also developed the patient-specific exercises including patient-passive exercise and patient-cooperative exercise, and the advantage of the developed patient-cooperative exercise is that we simplified the human-robot coupling system model into a single spring system instead of the mass-spring-damp system, which efficiently improved the response speed of the control system. In terms of the organization structure of the work, we introduced the end-effector type ULRR’s mechanical design, control system, inverse solution of positions, patient-passive exercise based on the inverse solution of positions and the linear position interpolation of servo drives, and patient-cooperative exercise based on the spring model, in sequence. Experiments with three healthy subjects have been conducted, with results showing good trajectory tracking performance in patient-passive exercise and showing effective, flexible, and good real-time interactive performance in patient-cooperative exercise.

Robot-assisted physical therapy can encourage a subject's voluntary participation to achieve rapid motor function recovery. To enhance the subject's cooperation, and training safety during training sessions, we develop a new ankle robotic system with three rehabilitation training strategies based on an admittance controller, namely, patient-passive compliance exercise, isotonic exercise, and patient-active exercise, which fully consider the patient's muscle strength level, and different stages of recovery. The developed parallel two-UPS/RRR ankle rehabilitation robot is actuated by two servo linear actuators, and one servo motor, and has three rotational degrees of freedom. The mechanism is simple, and ensures that the rotation center of the ankle joint complex from different patients coincides with the robot's rotation center. All three strategies are based on the admittance controller, and its derivatives, and the controller's output is obtained based on proportional, and time-shifting methods according to the continuous measured torque. In particular, the developed two-UPS/RRR ankle robotic system covers the whole-stage compliance rehabilitation training, ensuring the safety of full-cycle training sessions. Experiments of the three rehabilitation training strategies were carried out on five healthy subjects, with the results showing good compliance, and trajectory tracking performance.

Many chemotherapeutic drugs and photosensitizers suffer from poor solubility, unspecific delivery and uncontrollable release, which severely impede their biomedical applications. Herein, we designed a type of ROS-cleavable hydrophilic diselenide nanoparticles through self-assembling of PEG-modified camptothecin (CPT, a hydrophobic drug) and meso‑tetra (4-carboxyphenyl) porphine (TCPP, a hydrophobic photosensitizer). The TCPP@SeSe-CPT nanomedicine (particle size: 116.5 ± 1.9 nm) has stability for long-time blood circulation. Near-infrared (NIR) laser-triggered generation of ROS from TCPP can efficiently break the ROS-sensitive diselenide bond, which induces the decomposition of TCPP@SeSe-CPT nanomedicine for concurrent release of CPT and TCPP. Moreover, the released amounts of CPT and TCPP can be regulated by adjusting the NIR laser irradiation time. Such NIR-controlled release of CPT and TCPP can give rise to on-demand synergistic chemo-/photodynamic therapeutic effects for maximized tumor growth suppression with minimized side effects. STATEMENT OF SIGNIFICANCE: In this work, a ROS-cleavable diselenide nanoparticle was designed and successfully self-assembled with the hydrophobic drug camptothecin and photosensitizer TCPP into a hydrophilic TCPP@SeSe-CPT nanomedicine. Compared with traditional drug delivery systems, TCPP@SeSe-CPT nanomicelles could reduce premature drug release and co-deliver hydrophobic chemotherapeutic drugs/photosensitizers to tumors, which yielded a NIR-controlled synergistic chemo-/photodynamic therapeutic effect. Since diselenide bond is more sensitive than the traditional disulfide bond, under the 660 nm laser irradiation (300 mW/cm

It is widely accepted that a small particle size and rough surface can enhance tumor tissue accumulation and tumor cellular uptake of nanoparticles, respectively. Herein, sub-50 nm urchin-inspired disulfide bond-bridged mesoporous organosilica nanoparticles (UMONs) featured with a spiky surface and glutathione (GSH)-responsive biodegradability were successfully synthesized by a facile one-pot biphasic synthesis strategy for enhanced cellular internalization and tumor accumulation. l-Arginine (LA) is encapsulated into the mesopores of UMONs, whose outer surface is capped with the gatekeeper of ultrasmall gold nanoparticles, i.e., UMONs-LA-Au. On the one hand, the mild acidity-activated uncapping of ultrasmall gold can realize a tumor microenvironment (TME)-responsive release of LA. On the other hand, the unique natural glucose oxidase (GOx)-mimicking catalytic activity of ultrasmall gold can catalyze the decomposition of intratumoral glucose to produce acidic hydrogen peroxide (H2O2) and gluconic acid. Remarkably, these products can not only further facilitate the release of LA, but also catalyze the LA-H2O2 reaction for an increased nitric oxide (NO) yield, which realizes synergistic catalysis-enhanced NO gas therapy for tumor eradication. The judiciously fabricated UMONs-LA-Au present a paradigm of TME-responsive nanoplatforms for both enhanced cellular uptake and tumor-specific precision cascaded therapy, which broadens the range of practical biomedical applications and holds a significant promise for the clinical translation of silica-based nanotheranostics.

There is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial biofilm infections. Here, a novel "gas-sensitized hyperthermia" strategy is proposed for appreciable bacteria killing by the smart design of a metal-organic framework (MOF)-sealed Prussian blue-based nanocarrier (MSDG). Once the biofilm microenvironment (BME) is reached, the acidity-activated MOF degradation allows the release of diallyl trisulfide and subsequent glutathione-responsive generation of hydrogen sulfide (H

In order to better perform rehabilitation training on the ankle joint complex in the direction of dorsiflexion/plantarflexion and inversion/eversion, especially when performing the isokinetic muscle strength exercise, we need to calibrate the kinematic model to improve its control precision. The ankle rehabilitation robot we develop is a parallel mechanism, with its movements in the two directions driven by two linear motors. Inverse solution of positions is deduced and the output lengths of the two UPS kinematic branches are calibrated in the directions of dorsiflexion, plantarflexion, inversion, and eversion, respectively. Motion of each branch in different directions is fitted in high-order form according to experimental data. Variances, standard deviation, and goodness of fit are taken into consideration when choosing the best fitting curve, which ensures that each calibration can match the most appropriate fitting curve. Experiments are conducted to verify the effectiveness of the kinematic calibration after finishing the calibration, and the errors before and after calibration of the two kinematic chains in different directions are compared, respectively, which shows that the accuracy after calibration has been significantly improved.

Purpose The purpose of this paper is to implement a passive compliance training strategy for our newly designed 2-UPS/RRR parallel ankle rehabilitation robot (PARR) to enhance its rehabilitation training safety. Design/methodology/approach First, a kinematic analysis of the PARR is introduced, and the mechanism ensures that the rotation centre of the ankle joint complex (AJC) coincides with robot’s rotation centre. Then, a passive compliance training strategy based on admittance control is described in detail and is implemented on our PARR. Findings Experiments involving healthy subjects were conducted, and the performance of trajectory tracking was quantitatively evaluated, with the results showing excellent compliance and trajectory tracking accuracy, which can ensure that a secondary injury to the AJC during passive rehabilitation training is avoided. The influence of different admittance parameters was also simulated and analysed, which can contribute to the development of adaptive parameter adjustment research. Originality/value The paper can be used to improve the effectiveness of ankle rehabilitation, to alleviate manual therapy problems in terms of labour intensiveness, precision and subjectivity and to ensure safety and comfort during rehabilitation sessions.

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT-induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell-killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG-Py NPs) prepared by using a 2-pyridone-based diblock polymer (PEG-Py) to encapsulate a semiconducting, heavy-atom-free pyrrolopyrrolidone-tetraphenylethylene (DPPTPE) with high singlet-oxygen-generation ability both in dichloromethane and water. The PEG-Py can trap the 1 O2 generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release 1 O2 in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence-imaging-guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.

The clinical employment of cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is largely constrained due to the non-specific delivery and resultant serious systemic toxicity. Small-sized biocompatible and biodegradable hollow mesoporous organosilica (HMOS) nanoparticles show superior advantages for targeted CDDP delivery but suffer from premature CDDP leakage. Herein, the smart use of a bimetallic Zn

Hollow mesoporous organosilica nanoparticles (HMONs) are widely considered as a promising drug nanocarrier, but the loaded drugs can easily leak from HMONs, resulting in the considerably decreased drug loading capacity and increased biosafety risk. This study reports the smart use of core/shell Fe3O4/Gd2O3 (FG) hybrid nanoparticles as a gatekeeper to block the pores of HMONs, which can yield an unreported large loading content (up to 20.4%) of DOX. The conjugation of RGD dimer (R2) onto the DOX-loaded HMON with FG capping (D@HMON@FG@R2) allowed for active tumor-targeted delivery. The aggregated FG in D@HMON@FG@R2 could darken the normal tissue surrounding the tumor due to the high r2 value (253.7 mM-1 s-1) and high r2/r1 ratio (19.13), and the intratumorally released FG as a result of reducibility-triggered HMON degradation could brighten the tumor because of the high r1 value (20.1 mM-1 s-1) and low r2/r1 ratio (7.01), which contributed to high contrast magnetic resonance imaging (MRI) for guiding highly efficient tumor-specific DOX release and chemotherapy.

Radiation therapy (RT) and photodynamic therapy (PDT) are promising while challenging in treating tumors. The potential radiation resistance of tumor cells and side effects to healthy tissues restrict their clinical treatment efficacy. Effective delivery of therapeutic agents to the deep tumor tissues would be available for tumor-accurate therapy and promising for the tumor therapy. Thus, developing nanoprobes with effectively delivering radiotherapy sensitizers and photosensitizers to the interior of tumors is needed for the accurate combined RT and PDT of tumor.The size-changeable nanoprobes of GdThe nanoprobes BGBC showed high tumor accumulation and disintegrated into small particles responding to the photo-irradiation-produced reactive oxygen species (ROS), allowing for tumor penetration. Abundant radiotherapy sensitizers and photosensitizers were delivered to the deep tumor tissues, which is available for the accurate therapy of tumor. In addition, the BGBC displayed outstanding MRI and fluorescence imaging effects for evaluating the biodistribution and tumor suppression effect of nanoprobes. Consequently, significant tumor suppression effect was obtained based on the accurate tumor treatment with the combined RT and PDT.The designed size-changeable nanoprobes BGBC showed excellent tumor accumulation and deep tumor penetration, resulting in a significant tumor suppression effect based on the combined RT and PDT. This study provides a novel strategy for dual delivery of radiotherapy sensitizers and photosensitizers into the deep tumor tissues and is promising for the accurate theranostics of tumor.

Phototheranostics refers to advanced photonics-mediated theranostic methods for cancer and includes imaging-guided photothermal/chemotherapy, photothermal/photodynamic therapy, and photodynamic/chemotherapy, which are expected to provide a paradigm of modern precision medicine. In this regard, various phototheranostic drug delivery systems with excellent photonic performance, controlled drug delivery/release, and precise photoimaging guidance have been developed. In this study, we reported a special "in situ framework growth" method to synthesize novel phototheranostic hollow mesoporous nanoparticles by ingenious hybridization of perylene diimide (PDI) within the framework of small-sized hollow mesoporous organosilica (HMO). The marriage of PDI and HMO endowed the phototheranostic silica nanoparticles (HMPDINs) with largely amplified fluorescence and photoacoustic signals, which can be used for enhanced fluorescence and photoacoustic imaging. The organosilica shell can be chemically chelated with isotope 64Cu for positron emission tomography imaging. Moreover, in situ polymer growth was introduced in the hollow structure of the HMPDINs to produce thermosensitive polymer (TP) in the cavity of HMPDINs to increase the loading capacity and prevent unexpected leakage of the hydrophobic drug SN38. Furthermore, the framework-hybridized PDI generated heat under near-infrared laser irradiation to trigger the deformation of TP for controlled drug release in the tumor region. The fabricated hybrid nanomedicine with organic-inorganic characteristic not only increases the cancer theranostic efficacy but also offers an attractive solution for designing powerful theranostic platforms.

Nanomedicine has become a promising approach to improve cancer chemotherapy. It remains a major challenge how to enhance anti-drug efficacy and reduce side effects of anti-cancer drugs. Herein, we report a self-assembled nanoplatform (FDEP NPs) by integration of doxorubicin (DOX) and epigallocatechin-3-O-gallate (EGCG) with the help of coordination between Fe 3+ ions and polyphenols. The EGCG from FDEP NPs could inhibit the expression of carbonyl reductase 1 (CBR1) protein and thereby inhibit the doxorubicinol (DOXOL) generation from DOX both in vitro and in vivo , thus the efficacy of DOX to cancerous cells is improved significantly. More importantly, the FDEP NPs could reduce cardiac toxicity and the DOX mediated toxicity to blood cells due to the repression of DOXOL production. Moreover, the blood half-life of FDEP NPs is longer than 23 h as determined by positron emission tomography (PET) imaging of biodistribution of radiolabelled NPs and HPLC measurement of plasma level of DOX, ensuring high tumor accumulation of FDEP NPs by enhanced permeability and retention (EPR) effect. The FDEP NPs also exhibited much improved antitumor effect over free drugs. Our work sheds new light on the engineering of nanomaterials for combination chemotherapy and may find unique clinical applications in the near future.

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. Here we report an ammonia-assisted hot water etching strategy for the generic synthesis of a library of small-sized (sub-50 nm) hollow mesoporous organosilica nanoparticles (HMONs) with mono, double, triple, and even quadruple framework hybridization of diverse organic moieties by changing only the introduced bissilylated organosilica precursors. The biodegradable thioether-hybridized HMONs are chosen for efficient co-delivery of tert-butyl hydroperoxide (TBHP) and iron pentacarbonyl (Fe(CO)5). Distinct from conventional RT, radiodynamic therapy (RDT) is developed by taking advantage of X-ray-activated peroxy bond cleavage within TBHP to generate •OH, which can further attack Fe(CO)5 to release CO molecules for gas therapy. Detailed in vitro and in vivo studies reveal the X-ray-activated cascaded release of •OH and CO molecules from TBHP/Fe(CO)5 co-loaded PEGylated HMONs without reliance on oxygen, which brings about remarkable destructive effects against both normoxic and hypoxic cancers., A common failure of many cancer treatments is attributed to the resistance imparted by tumour hypoxia. Here, the authors report on the generic synthesis of small-sized hollow mesoporous organosilica nanoparticles which are designed for oxygen-independent X-ray-activated synergistic therapy.

Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood-brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.

It remains a major challenge to achieve precise on-demand drug release. Here, we developed a modular nanomedicine integrated with logic-gated system enabling programmable drug release for on-demand chemotherapy. Methods: We employed two different logical AND gates consisting of four interrelated moieties to construct the nanovesicles, denoted as v-A-CED2, containing oxidation-responsive nanovesicles (v), radical generators (A), and Edman linker conjugated prodrugs (CED2). The first AND logic gate is connected in parallel by mild hyperthermia ( I ) and acidic pH ( II ), which executes NIR laser triggered prodrug-to-drug transformation through Edman degradation. Meanwhile, the mild hyperthermia effect triggers alkyl radical generation ( III ) which contributes to internal oxidation and degradation of nanovesicles ( IV ). The second AND logic gate is therefore formed by the combination of I-IV to achieve programmable drug release by a single stimulus input NIR laser. The biodistribution of the nanovesicles was monitored by positron emission tomography (PET), photoacoustic, and fluorescence imaging. Results: The developed modular nanovesicles exhibited high tumor accumulation and effective anticancer effects both in vitro and in vivo. Conclusions: This study provides a novel paradigm of logic-gated programmable drug release system by a modular nanovesicle, which may shed light on innovation of anticancer agents and strategies.

The design of hybrid metal-organic framework (MOF) nanomaterials by integrating inorganic nanoparticle into MOF (NP@MOF) has demonstrated outstanding potential for obtaining enhanced, collective, and extended novel physiochemical properties. However, the reverse structure of MOF-integrated inorganic nanoparticle (MOF@NP) with multifunction has rarely been reported. Methods: We developed a facile in-situ growth method to integrate MOF nanoparticle into inorganic nanomaterial and designed a fluorescence switch to trigger enhanced photodynamic therapy. The influence of “switch” on the photodynamic activity was studied in vitro. The in vivo mice with tumor model was applied to evaluate the “switch”-triggered enhanced photodynamic therapy efficacy. Results: A core-satellites structure with fluorescence off and on function was obtained when growing MnO2 on the surface of fluorescent zeolitic imidazolate framework (ZIF-8) nanoparticles. Furthermore, A core-shell structure with photodynamic activity off and on function was achieved by growing MnO2 on the surface of porphyrinic ZrMOF nanoparticles (ZrMOF@MnO2). Both the fluorescence and photodynamic activities can be turned off by MnO2 and turned on by GSH. The GSH-responsive activation of photodynamic activity of ZrMOF@MnO2 significantly depleted the intracellular GSH via a MnO2 reduction reaction, thus triggering an enhanced photodynamic therapy efficacy. Finally, the GSH-reduced Mn2+ provided a platform for magnetic resonance imaging-guided tumor therapy. Conclusion: This work highlights the impact of inorganic nanomaterial on the MOF properties and provides insight to the rational design of multifunctional MOF-inorganic nanomaterial complexes.

Background The ankle joint complex (AJC) is of fundamental importance for balance, support, and propulsion. However, it is particularly susceptible to musculoskeletal and neurological injuries, especially neurological injuries such as drop foot following stroke. An important factor in ankle dysfunction is damage to the central nervous system (CNS). Correspondingly, the fundamental goal of rehabilitation training is to stimulate the reorganization and compensation of the CNS, and to promote the recovery of the motor system’s motor perception function. Therefore, an increasing number of ankle rehabilitation robots have been developed to provide long-term accurate and uniform rehabilitation training of the AJC, among which the parallel ankle rehabilitation robot (PARR) is the most studied. The aim of this study is to provide a systematic review of the state of the art in PARR technology, with consideration of the mechanism configurations, actuator types with different trajectory tracking control techniques, and rehabilitation training methods, thus facilitating the development of new and improved PARRs as a next step towards obtaining clinical proof of their rehabilitation benefits. Methods A literature search was conducted on PubMed, Scopus, IEEE Xplore, and Web of Science for articles related to the design and improvement of PARRs for ankle rehabilitation from each site’s respective inception from January 1999 to September 2020 using the keywords “ parallel”, “ ankle”, and “ robot”. Appropriate syntax using Boolean operators and wildcard symbols was utilized for each database to include a wider range of articles that may have used alternate spellings or synonyms, and the references listed in relevant publications were further screened according to the inclusion criteria and exclusion criteria. Results and discussion Ultimately, 65 articles representing 16 unique PARRs were selected for review, all of which have developed the prototypes with experiments designed to verify their usability and feasibility. From the comparison among these PARRs, we found that there are three main considerations for the mechanical design and mechanism optimization of PARRs, the choice of two actuator types including pneumatic and electrically driven control, the covering of the AJC’s motion space, and the optimization of the kinematic design, actuation design and structural design. The trajectory tracking accuracy and interactive control performance also need to be guaranteed to improve the effect of rehabilitation training and stimulate a patient’s active participation. In addition, the parameters of the reviewed 16 PARRs are summarized in detail with their differences compared by using figures and tables in the order they appeared, showing their differences in the two main actuator types, four exercise modes, fifteen control strategies, etc., which revealed the future research trends related to the improvement of the PARRs. Conclusion The selected studies showed the rapid development of PARRs in terms of their mechanical designs, control strategies, and rehabilitation training methods over the last two decades. However, the existing PARRs all have their own pros and cons, and few of the developed devices have been subjected to clinical trials. Designing a PARR with three degrees of freedom (DOFs) and whereby the mechanism’s rotation center coincides with the AJC rotation center is of vital importance in the mechanism design and optimization of PARRs. In addition, the design of actuators combining the advantages of the pneumatic-driven and electrically driven ones, as well as some new other actuators, will be a research hotspot for the development of PARRs. For the control strategy, compliance control with variable parameters should be further studied, with sEMG signal included to improve the real-time performance. Multimode rehabilitation training methods with multimodal motion intention recognition, real-time online detection and evaluation system should also be further developed to meet the needs of different ankle disability and rehabilitation stages. In addition, the clinical trials are in urgent need to help the PARRs be implementable as an intervention in clinical practice.

The outcome of radiotherapy is significantly restricted by tumor hypoxia. To overcome this obstacle, one prevalent solution is to increase intratumoral oxygen supply. However, its effectiveness is often limited by the high metabolic demand for O2 by cancer cells. Herein, we develop a hybrid semiconducting organosilica-based O2 nanoeconomizer pHPFON-NO/O2 to combat tumor hypoxia. Our solution is twofold: first, the pHPFON-NO/O2 interacts with the acidic tumor microenvironment to release NO for endogenous O2 conservation; second, it releases O2 in response to mild photothermal effect to enable exogenous O2 infusion. Additionally, the photothermal effect can be increased to eradicate tumor residues with radioresistant properties due to other factors. This “reducing expenditure of O2 and broadening sources” strategy significantly alleviates tumor hypoxia in multiple ways, greatly enhances the efficacy of radiotherapy both in vitro and in vivo, and demonstrates the synergy between on-demand temperature-controlled photothermal and oxygen-elevated radiotherapy for complete tumor response., Tumor hypoxia is a major limitation in radiotherapy, and strategies to address this often fail due to high oxygen consumption. Here, the authors report a nanomaterial assembly for the simultaneous reduction in mitochondrial respiration and to supply oxygen to potentiate radiotherapy.

Inhibiting the myofibroblast differentiation of lung-resident mesenchymal stem cells (LR-MSCs) is a promising yet challenging approach for pulmonary fibrosis (PF) therapy. Here, micelles formed by a graft copolymer of multiple PEGs modified branched polyethylenimine are used for delivering runt-related transcription factor-1 (RUNX1) small interfering RNA (siRNA) (siRUNX1) to the lung, aiming to inhibit the myofibroblast differentiation of LR-MSCs. LR-MSC targeting is achieved by functionalizing the micelle surface with an anti-stem-cell antigen-1 antibody fragment (Fab'). Consequently, therapeutic benefits are obtained by successful suppression of myofibroblast differentiation of LR-MSCs in bleomycin-induced PF model mice treated with siRUNX1-loaded micelles. Furthermore, an excellent synergistic effect of PF therapy is achieved for this micelle system loaded siRUNX1 and glioma-associated oncogene homolog-1 (Gli1) small interfering RNA (siGli1), a traditional anti-PF siRNA of glioma-associated oncogene homolog-1. Hence, this work not only provides RUNX1 as a novel PF therapeutic target, but also as a promising dual siRNA-loaded nanocarrier system for the therapy of PF.

The combination of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS-mediated cancer treatment. Herein, we reported an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor to integrate the synergistic effect of PDT/CDT for enhancing ROS-mediated pancreatic ductal adenocarcinoma treatment. HPPH photosensitizer was hybridized within the framework of HMON via an “in situ framework growth” approach. Then, the hollow cavity of HMONs was exploited as a nanoreactor for “in situ polymerization” to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase-like nanozyme, converting glucose into H(2)O(2) to provide self-supplied H(2)O(2) for CDT. Meanwhile, Cu(2+)-tannic acid complexes were further deposited on the surface of HMONs (HMON-Au@Cu-TA) to initiate Fenton-like reaction to covert the self-supplied H(2)O(2) into •OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix (ECM), was loaded into HMON-Au@Cu-TA to enhance the penetration of HMONs and O(2) infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS-mediated anti-tumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.

Improving tumor accumulation and delivery efficiency is an important goal of nanomedicine. Neutrophils play a vital role in both chemically mediating inflammatory response through myeloperoxidase (MPO) and biologically promoting metastasis during inflammation triggered by the primary tumor or environmental stimuli. Herein, a novel theranostic nanomedicine that targets both the chemical and biological functions of neutrophils in tumor is designed, facilitating the enhanced retention and sustained release of drug cargos for improved cancer theranostics. 5-hydroxytryptamine (5-HT) is equipped onto nanoparticles (NPs) loaded with photosensitizers and Zileuton (a leukotriene inhibitor) to obtain MPO and neutrophil targeting NPs, denoted as HZ-5 NPs. The MPO targeting property of 5-HT modified NPs is confirmed by noninvasive positron emission tomography imaging studies. Furthermore, photodynamic therapy is used to initiate the inflammatory response which further mediated the accumulation and retention of neutrophil targeting NPs in a breast cancer model. This design renders a greatly improved theranostic nanomedicine for efficient tumor suppression, and more importantly, inhibition of neutrophil-mediated lung metastasis via the sustained release of Zileuton. This work presents a novel strategy of targeting neutrophils for improved tumor theranostics, which may open up new avenues in designing nanomedicine through exploiting the tumor microenvironment.

Biocatalytic reactions in living cells involve complex transformations in the spatially confined microenvironments. Inspired by biological transformation processes, we demonstrate effective biocatalytic cascade driven photodynamic therapy in tumor-bearing mice by the integration of an artificial enzyme (ultrasmall Au nanoparticles) with upconversion nanoparticles (NaYF4@NaYb0.92F4:Er0.08@NaYF4)zirconium/iron porphyrin metal-organic framework core-shell nanoparticles (UMOF NPs) which act as biocatalysts and nanoreactors. The construction of core-shell UMOF NPs are realized by using a unique "solvent-assisted self-assembly" method. The integration of ultrasmall AuNPs on the UMOFs matrix leads to glucose depletion, providing Au-mediated cancer therapy via glucose oxidase like catalytic activity. Meanwhile, the UMOF matrix acts as a near-infrared (NIR) light photon-activated singlet oxygen generator through a continuous supply of oxygen via hydrogen peroxide decomposition upon irradiation. Such kinds of biocatalysts offer exciting opportunities for biomedical, catalytical ,and energy applications.

Repetitive and intensive physiotherapy is indispensable to patients with ankle disabilities. Increasingly robot-assisted technology has been employed in the treatment to reduce the burden of the therapists and the related costs of the patients. This paper proposes a configuration of a wearable parallel mechanism to supplement the equipment selection for ankle rehabilitation. The kinematic analysis, i.e., the inverse position solution and Jacobian matrices, is elaborated. Several performance indices, including the reachable workspace index, motion isotropy index, force transfer index, and maximum torque index, are developed based on the derived kinematic solution. Moreover, according to the proposed kinematic configuration and wearable design concept, the mechanical structure that contains a basic machine-drive system and a multi-model position/force data collection system is designed in detail. Finally, the results of the performance evaluation indicate that the wearable parallel robot possesses sufficient motion isotropy, high force transfer performance, and large maximum torque performance within a large workspace that can cover all possible range of motion of human ankle complex, and is suitable for ankle rehabilitation.

Tumor-specific phototheranostics is conducive to realizing precise cancer therapy. Herein, we rationally designed a novel tumor microenvironment (TME)-responsive phototheranostic paradigm based on an excellent match-up of semiconducting polymer brush and polyoxometalate cluster (SPB@POM). On the one hand, the acidic TME could drive the self-assembly of SPB@POM into bigger aggregates for enhanced tumor retention and accumulation. On the other hand, the reductive TME could significantly enhance the NIR absorption of SPB@POM for significant improvement of photoacoustic imaging contrast and photothermal therapy efficacy. Therefore, the intelligent acidity/reducibility dual-responsive SPB@POM allows for remarkable phototheranostic enhancement under the unique TME, which serves as a representative paradigm of nanotechnology in the judicious design of organic/inorganic hybrid nanomaterials for precise tumor-specific phototheranostics with minimal side effects.

Despite the advantages of mesoporous silica nanoparticles (MSNs) in drug delivery, the inherent non-biodegradability seriously impedes the clinical translation of inorganic MSNs, so the current research focus has been turned to mesoporous organosilica nanoparticles (MONs) with higher biocompatibility and easier biodegradability. Recent remarkable advances in silica fabrication chemistry have catalyzed the emergence of a library of MONs with various structures and functions. This review will summarize the latest state-of-the-art studies on the precise control of morphology, structure, framework, particle size and pore size of MONs, which enables the precise synthesis of MONs with suitable engineering for precision stimuli-responsive drug delivery/release, bioimaging and synergistic therapy. Besides, the potential challenges about the future development of MONs are also outlooked with the intention of attracting more researchers to promote the clinical translation of MONs.

This article describes the fabrication of hollow manganese/cobalt oxide nanoparticles (MCO NPs) with a tunable size through a redox reaction and the Kirkendall effect for cancer imaging and drug delivery. MCO-70 NPs (with an average size of 70 nm) can act as glutathione (GSH)-responsive contrast agents for dual T1/T2-weighted magnetic resonance imaging (MRI). The degradation of MCO NPs by GSH led to the enhancement of their T1 and T2 signals by 2.24- and 3.43-fold compared with those of MCO NPs before degradation, respectively. Antitumor agents such as doxorubicin (Dox) could be encapsulated inside the cavity of the hollow MCO NPs (MCO-70-Dox) and be released in the presence of GSH. The MCO-70-Dox NPs showed good tumor growth inhibition effects in vitro and in vivo, and can be promising drug delivery vehicles and MRI contrast agents for tumor diagnosis and reporting drug release.

Designing nanomaterials with advanced functions and physical properties to improve cancer diagnosis and treatment has been an enormous challenge. In this work, we report the synthesis of magnetic gold nanowreaths (AuNWs) by combining wet-chemical synthesis with layer-by-layer self-assembly. The presence of Au branches, small junctions, and central holes in AuNWs led to improved photothermal effect compared with Au nanoring seeds and thick Au nanoring with smooth surface. The self-assembly of exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) on the surfaces of AuNWs not only effectively quenched the T1-weighted magnetic resonance imaging (MRI) ability due to the enhanced T2 decaying effect but also provided the responsiveness to glutathione (GSH). After intravenous injection, the T1 signal of magnetic AuNWs initially in the “OFF” state can be intelligently switched on in response to the relatively high GSH concentration in tumor, and the formation of larger assemblies of ES-MIONs improved thei...

Featuring high biocompatibility, the emerging field of gas therapy has attracted extensive attention in the medical and scientific communities. Currently, considerable research has focused on the gasotransmitter nitric oxide (NO) owing to its unparalleled dual roles in directly killing cancer cells at high concentrations and cooperatively sensitizing cancer cells to other treatments for synergistic therapy. Of particular note, recent state-of-the-art studies have turned our attention to the chemical design of various endogenous/exogenous stimuli-responsive NO-releasing nanomedicines and their biomedical applications for on-demand NO-sensitized synergistic cancer therapy, which are discussed in this Minireview. Moreover, the potential challenges regarding NO gas therapy are also described, aiming to advance the development of NO nanomedicines as well as usher in new frontiers in this fertile research area.

Alleviation of tumor hypoxia has been the premise for improving the effectiveness of radiotherapy, which hinges upon the advanced delivery and rapid release of oxygen within the tumor region. Herein, we propose a “bubble-enhanced oxygen diffusion” strategy to achieve whole tumor oxygenation for significant radiation enhancement based on the “bystander effect”. Toward this end, sub-50 nm CuS-modified and 64Cu-labeled hollow mesoporous organosilica nanoparticles were constructed for tumor-specific delivery of O2-saturated perfluoropentane (PFP). Through the aid of PFP gasification arising from NIR laser-triggered mild hyperthermia, simultaneous PET/PA/US multimodality imaging and rapid oxygen diffusion across the tumor can be achieved for remarkable hypoxic radiosensitization. Furthermore, the multifunctional oxygen-carrying nanotheranostics also allow for other oxygen-dependent treatments, thus greatly advancing the development of bubble-enhanced synergistic therapy platforms.

A new colorimetric sensor based on citrate-stabilized AuNPs was proposed for the rapid pesticide residue detection of both terbuthylazine (TBA) and dimethoate (DMT) with ultra-sensitivities and high selectivities. The detection mechanisms have been verified via FT-IR, UV–vis spectra, Zeta Potential, TEM and DLS. Under the optimized experimental conditions, 30 kinds of potential environmental pollutants have no interference on the TBA or DMT detection indicating the high selectivities of our AuNP-based colorimetric sensor. The limit of detections (LODs) of TBA and DMT by eye vision are respectively 0.3 μM and 20 nM, and those based on calculation (3σ/S) are 0.02 μM and 6.2 nM, respectively. The minimum detectable concentrations of TBA or DMT are much lower than the maximum residue limit (MRL) regulated by the governments of EU and China. The linear relationships of the UV–vis spectrometry demonstrate that our AuNP-based colorimetric sensor can be used for the quantitative analysis of TBA in the range of 0.1–0.9 μM, and DMT in the range of 1–40 nM. Finally, our AuNP-based colorimetric sensor is also verified to have a good practical applicability for TBA or DMT detection in the real environmental samples.

Epidemiological studies suggest that ambient particulate matter exposure may be a new risk factor of glaucoma, but it lacks solid experimental evidence to establish a causal relationship. In this study, young mice (4 weeks old) were exposed concentrated ambient PM2.5 (CAP) for 9 months, which is throughout most of the life span of a mouse under heavy pollution. CAP was introduced using a versatile aerosol concentration enrichment system which mimics natural PM2.5 exposure. CAP exposure caused a gradual elevation of intraocular pressure (IOP) and an increase in aqueous humor outflow resistance. In the conventional outflow tissues that regulates IOP, inducible nitric oxide synthase (iNOS) was up-regulated and 3-nitrotyrosine (3-NT) formation increased. At the cellular level, PM2.5 exposure increased the transendothelial electrical resistance of cells that control IOP (AAP cells). This is accompanied by increased reactive oxygen species (ROS), iNOS and 3-NT levels. Peroxynitrite scavenger MnTMPyP successfully treated the IOP elevation and restored it to normal levels by reducing 3-NT formation in outflow tissues. This study provides the novel evidence that in young mice, lifetime whole-body PM2.5 exposure has a direct toxic effect on intraocular tissues, which imposes a significant risk of IOP elevation and may initiate the development of ocular hypertension and glaucoma. This occurs as a result of protein nitration of conventional aqueous humor outflow tissues.