Nanotechnologies meeting natural sources:Engineered lipoproteins for precise brain disease theranostics

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity,from preventive and diagnostic to therapeutic fields.Lipoproteins,because of their inherent blood-brain barrier permeability and lesion-homing capability,have been identified as promising strategies for high-performance theranostics of brain diseases.However,the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes,which can be critical for individual therapeutics and clinical translation.To address these issues,lipoprotein-inspired nano drug-delivery systems(nano-DDSs),which have been learned from nature,have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions.In this review,the barriers in brain disease treatment,advantages of state-of-the-art lipoprotein-inspired nano-DDSs,and bio-interactions of such nano-DDSs are highlighted.Furthermore,the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized.Specifically,the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed.Finally,the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles,such as exosomes,cell membranes,and bacteria,are discussed.

Gastrointestinal cancers in the era of theranostics: Updates and future perspectives

Theranostics are one of the practical aspects of personalized medicine.This concept was designed to describe a material combining diagnosis,treatment and follow up of a disease.It evolved and included molecular targeting and nanotechnologies that incorporate both diagnosis and therapeutics.In this editorial,we are presenting briefly the concept and evolution of theranostics,highlighting many applications of theranostics in daily practice and discussing future perspectives and aspects of this model in gastrointestincal cancers.

Current update on nanoplatforms as therapeutic and diagnostic tools:A review for the materials used as nanotheranostics and imaging modalities

In the last decade,the use of nanotheranostics as emerging diagnostic and therapeutic tools for various diseases,especially cancer,is held great attention.Up to date,several approaches have been employed in order to develop smart nanotheranostics,which combine bioactive targeting on specific tissues as well as diagnostic properties.The nanotheranostics can deliver therapeutic agents by concomitantly monitor the therapy response in real-time.Consequently,the possibility of over-or under-dosing is decreased.Various non-invasive imaging techniques have been used to quantitatively monitor the drug delivery processes.Radiolabeling of nanomaterials is widely used as powerful diagnostic approach on nuclear medicine imaging.In fact,various radiolabeled nanomaterials have been designed and developed for imaging tumors and other lesions due to their efficient characteristics.Inorganic nanoparticles as gold,silver,silica based nanomaterials or organic nanoparticles as polymers,carbon based nanomaterials,liposomes have been reported asmultifunctional nanotheranostics.In this review,the imaging modalities according to their use in various diseases are summarized,providing special details for radiolabeling.In further,the most current nanotheranostics categorized via the used nanomaterials are also summed up.To conclude,this review can be beneficial for medical and pharmaceutical society as well as material scientists who work in the field of nanotheranostics since they can use this research as guide for producing newer and more efficient nanotheranostics.

Beyond Antibiotics:Photo/Sonodynamic Approaches for Bacterial Theranostics

Rapid evolution and propagation of multidrug resistance among bacterial pathogens are outpacing the development of new antibiotics,but antimicrobial photodynamic therapy(aPDT)provides an excellent alternative.This treatment depends on the interaction between light and photoactivated sensitizer to generate reactive oxygen species(ROS),which are highly cytotoxic to induce apoptosis in virtually all microorganisms without resistance concern.When replacing light with low-frequency ultrasonic wave to activate sensitizer,a novel ultrasounddriven treatment emerges as antimicrobial sonodynamic therapy(aSDT).Recent advances in aPDT and aSDT reveal golden opportunities for the management of multidrug resistant bacterial infections,especially in the theranostic application where imaging diagnosis can be accomplished facilely with the inherent optical characteristics of sensitizers,and the generated ROS by aPDT/SDT cause broad-spectrum oxidative damage for sterilization.In this review,we systemically outline the mechanisms,targets,and current progress of aPDT/SDT for bacterial theranostic application.Furthermore,potential limitations and future perspectives are also highlighted.

Magnetic resonance imaging-guided and targeted theranostics of colorectal cancer

Colorectal cancer(CRC)is the most common gastrointestinal tract cancer worldwide and is associated with high morbidity and mortality.The development of nanosized drug delivery systems has provided a new direction in CRC treatment.Among these systems,magnetic nanoparticle(MNP)-based multifunctional platforms provide a novel strategy for magnetic resonance imaging(MRI)-related cancer theranostics.At the beginning o f this original review,the carcinogenesis and treatment status o f CRC are summarized.Then,diversified preparation and functionalization methods of MNPs are systematically analyzed,followed by MRIinvolved theranostic strategies.The latest progress in MRI-mediated multimode diagnosis and image-guided targeted therapy in CRC management is the main focus.Finally,the major challenges in promoting MRI-induced precise theranostics of CRC in clinical practice are discussed.

Cryogenic Exfoliation of 2D Stanene Nanosheets for Cancer Theranostics

Stanene(Sn)-based materials have been extensively applied in industrial production and daily life,but their potential biomedical application remains largely unexplored,which is due to the absence of the appropriate and effective methods for fabricating Sn-based biomaterials.Herein,we explored a new approach combining cryogenic exfoliation and liquid-phase exfoliation to successfully manufacture two-dimensional(2D)Sn nanosheets(SnNSs).The obtained SnNSs exhibited a typical sheet-like structure with an average size of~100 nm and a thickness of~5.1 nm.After PEGylation,the resulting PEGylated SnNSs(SnNSs@PEG)exhibited good stability,superior biocompatibility,and excellent photothermal performance,which could serve as robust photothermal agents for multi-modal imaging(fluorescence/photoacoustic/photothermal imaging)-guided photothermal elimination of cancer.Furthermore,we also used first-principles density functional theory calculations to investigate the photothermal mechanism of SnNSs,revealing that the free electrons in upper and lower layers of SnNSs contribute to the conversion of the photo to thermal.This work not only introduces a new approach to fabricate 2D SnNSs but also establishes the SnNSs-based nanomedicines for photonic cancer theranostics.This new type of SnNSs with great potential in the field of nanomedicines may spur a wave of developing Sn-based biological materials to benefit biomedical applications.

Mitochondrial H_(2)S_(n)-Mediated Anti-Inflammatory Theranostics

The insistent demand for space-controllable delivery,which reduces the side effects of non-steroidal antiinflammatory drugs(NSAIDs),has led to the development of a new theranostics-based approach for anti-inflammatory therapy.The current anti-inflammatory treatments can be improved by designing a drug delivery system responsive to the inflammatory site biomarker,hydrogen polysulfide(H_(2)S_(n)).Here,we report a noveltheranostic agent 1(TA1),consisting of three parts:H_(2)S_(n)-mediated triggering part,a two-photon fluorophore bearing mitochondria targeting unit(Rhodol-TPP),and anti-inflammatory COX inhibitor(indomethacin).In vitro experiments showed that TA1 selectively reacts with H_(2)S_(n)to concomitantly release both Rhodol-TPP and indomethacin.Confocal-microscopy imaging of inflammation-inducedlive cells suggested that TA1 is localized in the mitochondria where the H_(2)S_(n)is overexpressed.The TA1 reacted with H_(2)S_(n)in the endogenous and exogenous H_(2)S_(n)environments and in lipopolysaccharide treated inflammatory cells.Moreover,TA1 suppressed COX-2 level in the inflammatory-induced cells and prostaglandin E 2(PGE2)level in blood serum from inflammation-induced mouse models.In vivo experiments with inflammation-induced mouse models suggested that TA1 exhibits inflammation-site-elective drug release followed by significant therapeutic e ects,showing its function as a theranostic agent,capable of both anti-inflammatory therapy and precise diagnosis.Theranostic behavior of TA1 is highly applicable in vivo model therapeutics for the inflammatory disease.

Nanomaterials incorporated ultrasound contrast agents for cancer theranostics

Nanotechnology provides various nanomaterials with tremendous functionalities for cancer diagnostics and therapeutics.Recently, theranostics has been developed as an alternative strategy for efficient cancer treatment through combination of imaging diagnosis and therapeutic interventions under the guidance of diagnostic results. Ultrasound(US) imaging shows unique advantages with excellent features of real-time imaging, low cost, high safety and portability, making US contrast agents(UCAs)an ideal platform for construction of cancer theranostic agents. This review focuses on the development of nanomaterials incorporated multifunctional UCAs serving as theranostic agents for cancer diagnostics and therapeutics, via conjugation of superparamagnetic iron oxide nanoparticles(SPIOs), Cu S nanoparticles, DNA, si RNA, gold nanoparticles(GNPs), gold nanorods(GNRs), gold nanoshell(GNS), graphene oxides(GOs), polypyrrole(PPy) nanocapsules, Prussian blue(PB) nanoparticles and so on to different types of UCAs. The cancer treatment could be more effectively and accurately carried out under the guidance and monitoring with the help of the achieved theranostic agents. Furthermore, nanomaterials incorporated theranostic agents based on UCAs can be designed and constructed by demand for personalized and accurate treatment of cancer, demonstrating their great potential to address the challenges of cancer heterogeneity and adaptation, which can provide alternative strategies for cancer diagnosis and therapeutics.

The engineering of doxorubicin-loaded liposome-quantum dot hybrids for cancer theranostics

Many studies have recently attempted to develop multifunctional nanoconstructs by integrating the superior fluores- cence properties of quantum dots （QD） with therapeutic capabilities into a single vesicle for cancer theranostics. Liposome- quantum dot （L-QD） hybrid vesicles have shown promising potential for the construction of multifunctional nanoconstructs for cancer imaging and therapy. To fulfil such a potential, we report here the further functionalization of L-QD hybrid vesi- cles with therapeutic capabilities by loading anticancer drug doxorubicin （Dox） into their aqueous core. L-QD hybrid vesi- cles are first engineered by the incorporation of TOPO-capped, CdSe/ZnS QD into the lipid bilayers of DSPC：Chol：DSPE- PEG2000, followed by Dox loading using the pH-gradient technique. The loading efficiency of Dox into L-QD hybrid vesicles is achieved up to 97%, comparable to liposome control. All these evidences prove that the incorporation of QD into the lipid bilayer does not affect Dox loading through the lipid membrane of liposomes using the pH-gradient technique. Moreover, the release study shows that Dox release profile can be modulated simply by changing lipid composition. In conclusion, the Dox-loaded L-QD hybrid vesicles presented here constitute a promising multifunctional nanoconstruct capable of transporting combinations of therapeutic and diagnostic modalities.

Triphenylamine-AIEgens photoactive materials for cancer theranostics

Triphenylamine(TPA)-based aggregation-induced emission luminogens(TPA-AIEgens),a type of photoactive material utilizing the typical TPA moiety,has recently attracted increasing attention for the diagnostics and treatment of tumors due to their remarkable chemo-physical performance in optoelectronic research.TPA-AIEgens are distinguished from other photoactive agents by their strong fluorescence,good sensitivity,high signal-to-noise ratio,resistance to photobleaching,and lack of high concentration or aggregation-caused fluoresce quenching effects.In this review,we summarize the current advancements and the biomedical progress of TPA-AIEgens in tumor theranostics.First,the design principles of TPAAIEgens photoactive agents as well as the advanced targeting strategies for nuclei,cell membranes,cell organelle and tumors were introduced,respectively.Next,the applications of TPA-AIEgens in tumor diagnosis and therapeutic techniques were reviewed.Last,the challenges and prospects of TPA-AIEgens for cancer therapy were performed.The given landscape of the TPA-AIEgens hereby is meaningful for the further design and utilization of the novel photoactive material,which could be beneficial for the development of clinic applications.

Light-driven sextuple theranostics:nanomedicine involving second near-infrared AIE-active Ir(Ⅲ)complex for prominent cancer treatment

Light-driven cancer theranostics has shown inexhaustible and vigorous vitality by virtue of its high efficacy,prominent controllability and noninvasiveness.Exploration of an all-round theranostic material simultaneously affording both multimodal diagnosis imaging and synergistic phototherapy would be an appealing yet significantly challenging task.Herein,a novel nanomedicine Ir@PPEG-MeEPO was ingeniously constructed by integrating beforehand1O2-charged amphiphilic polymer and well-tailored Ir(Ⅲ)complex IrDPTP,which was featured by second near-infrared(NIR-Ⅱ)aggregation-induced emission(AIE)tendency,efficient reactive oxygen species(ROS)generation,good photothermal conversion efficiency and high-performance hydrogen gas production.To the best of our knowledge,IrDPTP held the longest emission wavelength among all reported AIE Ir(Ⅲ)complexes.Moreover,Ir@PPEG-MeEPO was capable of controllably releasing ROS via triggered photothermal effect upon NIR irradiation,making it well-adapted to hypoxic environment of tumor.Those distinctive characteristics of Ir@PPEG-MeEPO endowed it with unprecedented performance on sextuple theranostics comprised of NIR-Ⅱfluorescence-photoacoustic-photothermal trimodal imaging and photodynamic-photothermal-hydrogen trimodal therapy,witnessed by the precise tumor diagnosis and complete tumor elimination.The study would open up new perspectives for the exploration of superior nanomedicine for practical cancer theranostics.

Aggregation-induced emission luminogens for in vivo molecular imaging and theranostics in cancer

Cancer is one of the most fatal diseases for decades.Aggregation-induced emission luminogens(AIEgens)have been recently used as molecular imaging or therapeutic agents in cancers,due to the advantages of large Stokes shift,high quantum yield,great biocompatibility,and strong photostability.AIEgens can specifically target different types of cancer via diverse targeting strategies.AIEgen-based fluorescence imaging,especially near-infrared imaging,demonstrated deep penetration and suitable signal-to-noise ratio,which allows reliable in vivo cancer imaging.Combined with other imaging modalities,AIEgen-based multimodal imaging could provide multidimensional cancer hallmarks from different perspectives.In addition,AIEgenbased phototherapy can be used for photodynamic therapy and photothermal therapy,which facilitate ablation of cancer cells with good biosafety and high therapeutic effects in vivo.AIEgens nanoparticles fabricated with some specific chemicals,drugs,or siRNA,could display synergistic therapeutic effects for cancers.This paper comprehensively describes the current status and future perspectives of AIEgens,which have showed a great potential for the future preclinical and clinical translation on in vivo molecular imaging and theranostics in cancer.

Self-assembled nanoformulations of paclitaxel for enhanced cancer theranostics

Chemotherapy has occupied the critical position in cancer therapy,especially towards the post-operative,advanced,recurrent,and metastatic tumors.Paclitaxel(PTX)-based formulations have been widely used in clinical practice,while the therapeutic effect is far from satisfied due to off-target toxicity and drug resistance.The caseless multi-components make the preparation technology complicated and aggravate the concerns with the excipients-associated toxicity.The self-assembled PTX nanoparticles possess a high drug content and could incorporate various functional molecules for enhancing the therapeutic index.In this work,we summarize the self-assembly strategy for diverse nanodrugs of PTX.Then,the advancement of nanodrugs for tumor therapy,especially emphasis on monochemotherapy,combinational therapy,and theranostics,have been outlined.Finally,the challenges and potential improvements have been briefly spotlighted.

Novel seven-membered ring-fused naphthalimide derivatives with potentials for cancer theranostics

Naphthalimide derivatives have good planarity and large conjugated structure and therefore possess photophysical properties and biological activities. Previously, our group discovered seven-membered heterocyclic derivatives via modifying 4-and 5-positions of naphthalimide skeleton and found the derivatives had good water solubility and showed large stokes shift and strong fluorescence in water. In this article, we designed and synthesized more seven-membered ring-fused naphthalimide derivatives(Y1-Y16)by introducing different substitutions on the imide group. Among them, Y1, Y5, Y9 were found to show similar cytotoxic activities with Amonafide against A549 and HL60 cells, with IC50values at 10^(-6)mol/L.What is more, the asymmetry derivatives(Y1 and Y5) showed high fluorescent quantum yields in the aqueous phase(Ф = 0.47). Considering the great fluorescence quantum yields in water and the potent anti-tumor activities of the representative seven-membered ring-fused naphthalimides, they have potentials to be used as agents for cancer theranostics.

Deep Insight of Design,Mechanism,and Cancer Theranostic Strategy of Nanozymes

Since the discovery of enzyme-like activity of Fe3O4 nanoparticles in 2007,nanozymes are becoming the promising substitutes for natural enzymes due to their advantages of high catalytic activity,low cost,mild reaction conditions,good stability,and suitable for large-scale production.Recently,with the cross fusion of nanomedicine and nanocatalysis,nanozyme-based theranostic strategies attract great attention,since the enzymatic reactions can be triggered in the tumor microenvironment to achieve good curative effect with substrate specificity and low side effects.Thus,various nanozymes have been developed and used for tumor therapy.In this review,more than 270 research articles are discussed systematically to present progress in the past five years.First,the discovery and development of nanozymes are summarized.Second,classification and catalytic mechanism of nanozymes are discussed.Third,activity prediction and rational design of nanozymes are focused by highlighting the methods of density functional theory,machine learning,biomimetic and chemical design.Then,synergistic theranostic strategy of nanozymes are introduced.Finally,current challenges and future prospects of nanozymes used for tumor theranostic are outlined,including selectivity,biosafety,repeatability and stability,in-depth catalytic mechanism,predicting and evaluating activities.

Pillararene-based supramolecular systems for theranostics and bioapplications

As an emerging type of important macrocycles for supramolecular chemistry,pillararenes and their derivatives have been widely studied and applied in numerous fields,which intensively promotes the development of chemistry,materials science and biology.Pillararene-based theranostic systems are of special interest in the biological and medical areas as they have shown very promising results.Owing to easy preparation,reliable guest affinity,good biocompatibility and stability,pillararenes are frequently used to construct functional biomaterials.On one hand,pillararenes can either be used individually or form diversiform self-assemblies such as micelles,nanoparticles and vesicles to increase water solubility and biocompatibility of drugs.On the other hand,it is promising to modify solid materials like framework materials,silica nanoparticles and graphene oxides with pillararene derivatives to enhance their functions and controllability.In this review,we summarize recent endeavors of pillararene-based supramolecular systems with theranostics and other biological applications comprising drug delivery/chemotherapy,photodynamic/photothermal therapy,antimicrobials,bioimaging,etc.By introducing several typical examples,the design principles,preparation strategies,identifications and bio-applications of these pillararene-based supramolecular systems are described.Future challenges and directions of this field are also outlined.

Cathepsin B-responsive and gadolinium-labeled branched glycopolymer-PTX conjugate-derived nanotheranostics for cancer treatment

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched glycopolymer.The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic effect.The theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h post-injection.Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity.This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

Biomimetic nanomedicine toward personalized disease theranostics

Despite nanoparticle-based drug delivery systems have aroused broad research interest in the biomedical fields,the rising challenges such as easy recognition by the immune system and low accumulation in diseased sites significantly hinder their further clinical translation.Nanoparticles wrapped in cell membrane have emerged as a distinctive strategy to overcome these limitations due to the superior marriage of natural cell membrane and artificial nanomaterials,which endow them with prominent advantages in disease diagnosis and treatment,such as targeted drug transport,prolonged drug half-life,and diminished immunogenicity and cytotoxicity.In this review,we mainly highlight and discuss the evolving progresses and advantages of cell membrane-based biomimetic nanosystems in the detection and treatment of various diseases over the past five years,including oncology,bacterial infections,brain diseases,and inflammatory diseases,which would benefit researchers in better and comprehensively understanding the complicated microenvironment of diseases and developing personalized biomimetic nanomedicines for different diseases.The current challenges and potential opportunities for the future clinical translation of cell membrane coating nanotechnology are also covered.

New insight into photoacoustic conversion efficiency by plasmon-mediated nanocavitation： Implications for precision theranostics

The probe-assisted integration of imaging and therapy into a single modality offers significant advantages in bio-applications. As a newly developed photoacoustic （PA） mechanism, plasmon-mediated nanocavitation, whereby photons are effectively converted into PA shockwaves, has excellent advantages for image-guided therapy. In this study, by simulating the laser absorption, temperature field, and nanobubble dynamics using both finite-element analysis and computational fluid dynamics, we quantified the cavitation-induced PA conversion efficiency of a water-immersed gold nanosphere, revealing new insights. Interestingly, sequential multi-bubble emission accompanied by high PA signal production occur under a single high-dose pulse of laser irradiation, enabling a cavitation-induced PA conversion efficiency up to 2%, which is -50 times higher than that due to thermal expansion. The cavitation-induced PA signal has unique frequency characteristics, which may be useful for a new approach for in vivo nanoparticle tracking. Our work offers theoretical guidance for accurate diagnosis and controllable therapy based on plasmon-mediated nanocavitation.

Iron oxide nanoparticle-based theranostics for cancer imaging and therapy

Theranostic platform, which is equipped with both diagnostic and therapeutic functions, is a promising approach in cancer treatment. From various nanotheranostics studied, iron oxide nanoparticles have advantages since IONPs have good biocompatibility and spatial imaging capability. This review is focused on the IONP- based nanotheranostics for cancer imaging and treatment. The most recent progress for applications of IONP nanotheranostics is summarized, which includes IONP- based diagnosis, magnetic resonance imaging （MRI）, multimodal imaging, chemotherapy, hyperthermal therapy, photodynamic therapy, and gene delivery. Future perspectives and challenges are also outlined for the potential development of IONP based theranostics in clinical use.