Theranostic applications:Non-ionizing cellular and molecular imaging through innovative nanosystems for early diagnosis and therapy

Modern medicine is expanding the possibilities of receiving "personalized" diagnosis and therapies,providing minimal invasiveness,technological solutions based on non-ionizing radiation,early detection of pathologies with the main objectives of being operator independent and with low cost to society.Our research activities aim to strongly contribute to these trends by improving the capabilities of current diagnostic imaging systems,which are of key importance in possibly providing both optimal diagnosis and therapies to patients.In medical diagnostics,cellular imaging aims to develop new methods and technologies for the detection of specific metabolic processes in living organisms,in order to accurately identify and discriminate normal from pathological tissues.In fact,most diseases have a "molecular basis" that detected through these new diagnostic methodologies can provide enormous benefits to medicine.Nowadays,this possibility is mainly related to the use of Positron Emission Tomography,with an exposure to ionizing radiation for patients and operators and with extremely high medical diagnosticscosts.The future possible development of non-ionizing cellular imaging based on techniques such as Nuclear Magnetic Resonance or Ultrasound,would represent an important step towards modern and personalized therapies.During the last decade,the field of nanotechnology has made important progress and a wide range of organic and inorganic nanomaterials are now available with an incredible number of further combinations with other compounds for cellular targeting.The availability of these new advanced nanosystems allows new scenarios in diagnostic methodologies which are potentially capable of providing morphological and functional information together with metabolic and cellular indications.

Intranasal administration nanosystems for brain-targeted drug delivery

The existence of the blood-brain barrier(BBB)restricts the entry of drugs from the circulation into the central nervous system(CNS),which severely affects the treatment of neurological diseases,including glioblastoma,Parkinson’s disease(PD),and Alzheimer’s disease(AD).With the advantage of bypassing the BBB and avoiding systemic distribution,intranasal administration has emerged as an alternative method of delivering drugs to the brain.Drug delivery directly to the brain using intranasal nanosystems represents a new paradigm for neurological disease treatment because of its advantages in improving drug solubility and stability in vivo,enabling targeted drug delivery and controlled release,and reducing non-specific toxicity.And it has shown efficacy in animal models and clinical applications.Herein,this review describes the mechanisms of intranasal delivery of brain-targeted drugs,the properties of nanosystems for intranasal administration(e.g.,liposomes,nanoemulsions,and micelles),and strategies for intranasal drug delivery to enhance brain-targeted drug delivery.Recent applications of nanosystems in intranasal drug delivery and disease treatment have been comprehensively reviewed.Although encouraging results have been reported,significant challenges still need to be overcome to translate these nanosystems into clinics.Therefore,the future prospects of intranasal drug delivery nanosystems are discussed in depth,expecting to provide useful insights and guidance for effective neurological disease treatment.

Supramolecular host-guest nanosystems for overcoming cancer drug resistance

Cancer drug resistance has become one of the main challenges for the failure of chemotherapy,greatly limiting the selection and use of anticancer drugs and dashing the hopes of cancer patients.The emergence of supramolecular host-guest nanosystems has brought the field of supramolecular chemistry into the nanoworld,providing a potential solution to this challenge.Compared with conventional chemotherapeutic platforms,supramolecular host-guest nanosystems can reverse cancer drug resistance by increasing drug uptake,reducing drug efflux,activating drugs,and inhibiting DNA repair.Herein,we summarize the research progress of supramolecular host-guest nanosystems for overcoming cancer drug resistance and discuss the future research direction in this field.It is hoped that this review will provide more positive references for overcoming cancer drug resistance and promoting the development of supramolecular host-guest nanosystems.

Smart Supramolecular Nanosystems for Bioimaging and Drug Delivery

The application of smart supramolecular nanosystems in biomedicine increases rapidly and offers promising prospects for disease diagnostics and therapeutics.Supramolecular nanosystems such as liposomes,micelles,or-ganic nanoaggregates and metallic nanostructures etc.have been widely explored as diagnostic/therapeutic tools.Here,we review the recent advances in supramolecular nanosystems with different builtin reporters,e.g.,fluorescent,magnetic and photoacoustic signals for bioimaging.In addition,the substantial progress of supramolecular nanosystems as drug delivery carriers for cancer therapy,including chemotherapy,photothermal and photodynamic therapies is also summarized.

Energy Harvesting for Self-Powered Nanosystems

In this article,an introduction is presented about the energy harvesting technologies that have potential for powering nanosystems.Our discussion mainly focuses on the approaches other than the well-known solar cell and thermoelectrics.We mainly introduce the piezoelectric nanogenerators developed using aligned ZnO nanowire arrays.This is a potential technology for converting mechanical movement energy(such as body movement,muscle stretching,blood pressure),vibration energy(such as acoustic/ultrasonic wave),and hydraulic energy(such as fl ow of body fl uid,blood fl ow,contraction of blood vessel,dynamic fl uid in nature)into electric energy for self-powered nanosystems.

Eu^(3+)-doped LaPO_4 and LaAlO_3 nanosystems and their luminescence properties

Eu3+ ion-doped LaPO4 nanowires or nanorods have been successfully synthesized by a simple hydrothermal method.The influence of varying the hydrothermal and subsequent sintering conditions on the morphology and structure of the LaPO4 host has been investigated by scanning electron microscopy(SEM) and X-ray diffraction(XRD).For comparison,the Eu3+ ions were also doped into monoclinic monazite LaPO4 nanoparticles and perovskite LaAlO3 nanoparticles.The relative intensities of the emission lines of the LaPO4:Eu3+ nanosystems were essentially independent of their shape.The optimal doping concentrations in the monoclinic LaPO4 and perovskite LaAlO3 nanosystems were determined to be about 5.0 and 3.5 mol%,respectively.Under appropriate UV-radiation,the red light emitted from LaAlO3:Eu3+(3.5 mol%) was brighter than that from LaPO4:Eu3+(5.0 mol%) nanomaterial,resulting from differences in their spin-orbit couplings and covalence,which indicates that the nanoscale LaAlO3 is a promising host material for rare earth ions.

From Proton Conductive Nanowires to Nanofuel Cells： A Powerful Candidate for Generating Electricity for Self-Powered Nanosystems

The likely goal of nanotectulology is the integration of individual nanodevices into a nanosystem, which includes the nanodevice（s）, power harvesting unit, data processing logic system, and possibly wireless communication unit. A nanosystem requires a nanoscale power source to make the entire package extremely small and high performance. The nanofuel and nanobiofuel cells developed here represent a new self-powering approach in nanotechnology, and their power output is high enough to drive nanodevices for performing self-powered sensing. This study shows the feasibility of building self-powered nanosystems for biological sciences, environmental monitoring, defense technology and even personal electronics.

Recent Advances in Directed Assembly of Nanowires or Nanotubes

Nanowires and nanotubes of diverse material compositions,properties and/or functions have been produced or fabricated through various bottom-up or top-down approaches.These nanowires or nanotubes have also been utilized as potential building blocks for functional nanodevices.The key for the integration of those nanowire or nanotube based devices is to assemble these one dimensional nanomaterials to specific locations using techniques that are highly controllable and scalable.Ideally such techniques should enable assembly of highly uniform nanowire/nanotube arrays with precise control of density,location,dimension or even material types of nanowires/nanotubes.Numerous assembly techniques are being developed that can quickly align and assemble large quantities of one type or multiple types of nanowires through parallel processes,including flow-assisted alignment,Langmuir-Blodgett assembly,bubble-blown technique,electric/magnetic-field directed assembly,contact/roll printing,knocking-down,etc..With these assembling techniques,applications of nanowire/nanotube based devices such as flexible electronics and sensors have been demonstrated.This paper delivers an overall review of directed nanowire/nanotube assembling approaches and analyzes advantages and limitations of each method.The future research directions have also been discussed.

Artificial Nanoscale Erythrocytes from Clinically Relevant Compounds for Enhancing Cancer Immunotherapy

Because of enhanced e cacy and lower side e ects,cancer immunotherapies have recently been extensively investigated in clinical trials to overcome the limitations of conventional cancer monotherapies.Although engineering attempts have been made to build nanosystems even including stimulus nanomaterials for the e cient delivery of antigens,adjuvants,or anticancer drugs to improve immunogenic cancer cell death,this requires huge R&D e orts and investment for clinically relevant findings to be approved for translation of the nanosystems.To this end,in this study,an air–liquid two-phase electrospray was developed for stable bubble pressing under a balance between mechanical and electrical parameters of the spray to continuously produce biomimetic nanosystems consisting of only clinically relevant compounds[paclitaxel-loaded fake blood cell Eudragit particle(Eu-FBCP/PTX)]to provide a conceptual leap for the timely development of translatable chemo-immunotherapeutic nanosystems.This was pursued as the e cacy of systems for delivering anticancer agents that has been mainly influenced by nanosystem shape because of its relevance to transporting behavior to organs,blood circulation,and cell–membrane interactions.The resulting Eu-FBCP/PTX nanosystems exhibiting phagocytic and micropinocytic uptake behaviors can confer better e cacy in chemo-immunotherapeutics in the absence and presence of anti-PD-L1 antibodies than similar sized PTX-loaded spherical Eu particles(Eu-s/PTX).

Nanotechnoscience as Combination of the Natural and Engineering Sciences

This paper discusses the methodological specialty of the theoretical investigation in the nanotechnology. In the nanotechnoscience, on the one hand, similar with the classical natural science are created explanatory schemes of the natural phenomena and formulated predictions of the course of the definite natural events on the basis of mathematics and experimental data, and on the other, as in the engineering sciences are constructed not only the projects of the new experimental situations but also structural schemes of the new nanosystem unknown in nature and technology. The operation of nanotheory is realized by the iteration method. At first a special engineering problem is formulated. Then it is represented in the form of the structural scheme of the nanosystem which is transformed into the idea about the natural process reflecting its performance. To calculate and mathematically model this process a functional scheme is constructed. Consequently, the engineering problem is reformulated into a scientific one and then into a mathematical problem solved by the deductive method. This path from the bottom to the top represents the analysis of schemes （the bottom up approach）. The way in the opposite direction--the synthesis of schemes （the top down approach）--makes it possible to synthesize the ideal model of a new nanosystem from idealized structural elements, according to the appropriate rules of deductive transformation, to calculate basic parameters of the nanosystem and simulate its function. Nanotechnology is at the same time a field of scientific knowledge and a sphere of engineering activity, in other words--nanotechnoscience--similar with systems engineering as the analysis and design of large-scale, complex, man-machine systems, but now as micro- and nanosystems. Scanning tunneling microscope in the nanoexperiment is not only an arrangement of scientific investigation but also at the same time a facility to fabricate the electrically conducting bridges between an electrode and the selected nanotubes and computer modeling and the design of different artifacts.

New Orbital-Free Approach for Density Functional Modeling of Large Molecules and Nanoparticles

Development of the orbital-free (OF) approach of the density functional theory (DFT) may result in a power instrument for modeling of complicated nanosystems with a huge number of atoms. A key problem on this way is calculation of the kinetic energy. We demonstrate how it is possible to create the OF kinetic energy functionals using results of Kohn-Sham calculations for single atoms. Calculations provided with these functionals for dimers of sp-elements of the C, Si, and Ge periodic table rows show a good accordance with the Kohn-Sham DFT results.

A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy

The combination of Ce6,an acknowledged photosensitizer,and TPL,a natural anticancer agent,has been demonstrated as a useful strategy to reinforce the tumor growth suppression,as well as decrease the systemic side effects compared with their monotherapy.However,in view of the optimal chemo-photodynamic combination efficiency,there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL,and stimuli-responsively burst release drugs in tumor site.Herein,we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem,mediated by the host–guest complexing betweenβ-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG,showing the shell–core structural micelles with the tightβ-CD layer coating.Both Ce6 and TPLwere facilely co-loaded into the spherical supramolecular NPs(TPL+Ce6/NPs)by one-step nanoprecipitation method,with an ideal particle size(156.0 nm),acid pH-responsive drug release profile,and enhanced cellular internalization capacity.In view of the combination benefit of photodynamic therapy and chemotherapy,as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs,TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation,boost ROS level,lower MMP,and promote cellular apoptosis in vitro.Particularly,fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area,with higher intensity than that of free Ce6.As expected,upon 650-nm laser irradiation,TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearingmice and B16 tumor-bearingmice.More importantly,lower systemic toxicitywas found in the tumor-bearingmice treated with TPL+Ce6/NPs.Overall,the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

Performance Analysis of an Artificial Intelligence Nanosystem with Biological Internet of Nano Things

Artificial intelligence(AI)has recently been used in nanomedical applications,in which implanted intelligent nanosystems inside the human body were used to diagnose and treat a variety of ailments with the help of the Internet of biological Nano Things(IoBNT).Biological circuit engineering or nanomaterial-based architectures can be used to approach the nanosystem.In nanomedical applications,the blood vascular medium serves as a communication channel,demonstrating a molecular communication system based on flow and diffusion.This paper presents a performance study of the channel capacity for flow-based-diffusive molecular communication nanosystems that takes into account the ligand-receptor binding mechanism.Unlike earlier studies,we take into account the effects of biological physical characteristics such as blood pressure,blood viscosity,and vascular diameter on channel capacity.Furthermore,in terms of drug transmission error probability,the inter-symbol interference(ISI)phenomenon is applied to the proposed system.The numerical results show that the proposed AI nanosystems-based IoBNT technology can be successfully implemented in future nanomedicine.

Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy

Tumor cells establish a robust self-defense system characterized by hypoxia,antioxidant overexpression,DNA damage repair,and so forth to resist radiotherapy.Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy.Therefore,we herein developed an engineering biomimetic nanosystem(M@HHPt)masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens(O_(2))and cisplatin prodrugs(Pt(Ⅳ))to target multiple tumor radioresistance hallmarks for enhanced radiotherapy.After administration,M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O_(2)and Pt(Ⅳ).O_(2)introduction induced hypoxia alleviation cooperated with Pt(Ⅳ)reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress.Moreover,the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments.Consequently,M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%.Overall,this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

Nanosystem-mediated lactate modulation in the tumor micro environment for enhanced cancer therapy

Metabolic reprogramming allows tumor cells to prefer aerobic glycolysis as the main energy source,resulting in the massive accumulation of lactate in the tumor microenvironment(TME).It is found that lactate is no longer a waste product produced by glycolysis,but plays an important role in cancer progression.The modulation of lactate in the TME has become a promising target for cancer therapy.Although many small molecular inhibitors modulating the production or transport of lactate have appeared at present,their safety and efficacy have limited their further clinical application due to their non-specific targets and biodistribution.Studies have shown that nanomedicine has unique advantages,improving drug delivery efficiency and treatment efficacy while reducing damage to normal tissues,which greatly promotes the development of the research of nanosystems based on lactate modulation.In this review,we summarize the source and metabolism of lactate,the effect of lactate on the TME and recent advances in nanosystem-mediated strategies of lactate modulation for enhanced cancer therapy,hoping to provide ideas and directions for future research in related fields.

Effective Qubit Emerging from the Nanoheterointerface Two-Dimensional Electron Gas Photodynamics

An “Eigenstate Adjustment Autonomy” Model, permeated by the Nanosystem’s Fermi Level Pinning along with its rigid Conduction Band Discontinuity, compatible with pertinent Experimental Measurements, is being employed for studying how the Functional Eigenstate of the Two-Dimensional Electron Gas (2DEG) dwelling within the Quantum Well of a typical Semiconductor Nanoheterointerface evolves versus (cryptographically) selectable consecutive Cumulative Photon Dose values. Thus, it is ultimately discussed that the experimentally observed (after a Critical Cumulative Photon Dose) Phenomenon of 2DEG Negative Differential Mobility allows for the Nanosystem to exhibit an Effective Qubit Specific Functionality potentially conducive to (Telecommunication) Quantum Information Registering.

A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

Leveraging nano-engineered mesenchymal stem cells for intramedullary spinal cord tumor treatment

Intramedullary spinal cord tumor(IMSCT)is comparatively rare malignant tumor in the central nervous system and is very difficult accessible by conventional chemotherapy regimen.Currently,there are very limited researches for IMSCT treatment using nanomedicine.To fill this gap,we originally reported a targeted strategy by leveraging nano-engineered mesenchymal stem cells(MSCs)for synergistic antiIMSCT treatment.In this study,two mode drugs paclitaxel(PTX)and metformin(MET)were co-loaded in maleimide-modified poly(lactic-co-glycolicacid)(PLGA-MAL)nanoparticles,which were further conjugated onto MSCs surface via the thioether bond formed between PLGA-MAL and MSCs without affecting the migration ability of MSCs.Owing to the excellent tumor tropism and penetrability of MSCs and good biodegradability of PLGA,the designed drug delivery platform could accurately target IMSCT sites to exert long-term synergistic antitumor efficacy,exhibiting promising research value for alternative IMSCT management beyond surgery.

Probes and nano-delivery systems targeting NAD(P)H:quinone oxidoreductase 1:a mini-review

The two-electron cytoplasmic reductase NAD(P)H:quinone oxidoreductase 1 is expressed in many tissues.NAD(P)H:quinone oxidoreductase 1 is well-known for being highly expressed in most cancers.Therefore,it could be a target for cancer therapy.Because it is a quinone reductase,many bioimaging probes based on quinone structures target NAD(P)H:quinone oxidoreductase 1 to diagnose tumours.Its expression is higher in tumours than in normal tissues,and using target drugs such asβ-lapachone to reduce side effects in normal tissues can help.However,the physicochemical properties ofβlapachone limit its application.The problem can be solved by using nanosystems to deliverβ-lapachone.This minireview summarizes quinone-based fluorescent,nearinfrared and two-photon fluorescent probes,as well as nanosystems for delivering the NAD(P)H:quinone oxidoreductase 1-activating drugβ-lapachone.This review provides valuable information for the future development of probes and nano-delivery systems that target NAD(P)H:quinone oxidoreductase 1.

A soluble pH-responsive host-guest-based nanosystem for homogeneous exosomes capture with high-efficiency

Exosomes offer ideal biomarkers for liquid biopsies.However,high-efficient capture of exosomes has been proven to be extreme challenging.Here,we report a soluble pH-responsive host-guest-based nanosystem(pH-HGN)for homogeneous isolation of exosomes around physiological pH.The pH-HGN consists of two specifically functionalized modules.First,a pH-responsive module,poly-dimethylaminoethyl methacrylate,provides homogeneous capture circumstances and sharp pH-triggered self-assembly separation in aqueous solution to improve capture efficiency and reduce nonspecific adsorption.Second,a host-guest module,poly-acrylamide azobenzene andβ-cyclodextrin linked with exosomes-specific antibody,could act as the"cleavable bridge"to specific capture and subsequent rapid release of captured exosomes through host-guest interaction betweenβ-cyclodextrin and AAAB moieties.The pH-HGN offered high capture efficiencies for exosomes from two different cell lines,which were 90.2%±0.28%and 87.0%±4.6%for H1299 and MCF-7 cell-derived exosomes,respectively.The purity of isolated exosomes was(1.49±0.71)×10^(11)particles/μg,which was 4.1 times higher compared with the gold standard ultracentrifugation(UC)method.Furthermore,the isolated exosomes via the pH-HGN can preserve well integrity and biological activity.The developed pH-HGN was further successfully applied to differentiate lung cancer patients from healthy persons.These findings indicated that pH-HGN is a promising strategy in exosomes-based research and downstream applications.