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.

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.

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.

Recent advances in copper homeostasis-involved tumor theranostics

As the third essential trace element in the human body,copper plays a crucial role in various physiological processes,which lays the foundation for its broad applications in cancer treatments.The overview of copper,including pharmacokinetics,signaling pathways,and homeostasis dysregulation,is hereby discussed.Additionally,cuproptosis,as a newly proposed cell death mechanism associated with copper accumulation,is analyzed and further developed for efficient cancer treatment.Different forms of Cu-based nanoparticles and their advantages,aswell as limiting factors,are introduced.Moreover,the unique characteristics of Cu-based nanoparticles give rise to their applications in various imaging modalities.In addition,Cu-based nanomaterials are featured by their excellent photothermal property and ROS-associated tumor-killing potential,which are widely explored in diverse cancer therapies and combined therapies.Reducing the concentration of Cu^(2+)/Cu^(+)is another cancer-killing method,and chelators can meet this need.More importantly,challenges and future prospects are identified for further research.

Porphyrin-based metal-organic frameworks for cancer theranostics

Theranostics,integrating diagnostic and therapeutic functionalities,have emerged as advanced systems for timely cancer diagnosis and effective treatment.The development of versatile materials suitable for cancer theranostics is intensifying.Porphyrin-based metal-organic frameworks(MOFs)leverage the structural diversity and designability inherent in MOFs,alongside the robust photophysical,catalytic,and biological properties of porphyrins.These materials enhance the solubility and stability of porphyrins and facilitate their stable functionalized assemblies,conferring the potential for multimodal imaging diagnostics and precision therapeutics.In this review,we summarized the potential of porphyrin-based MOFs as cancer theranostics platforms,focusing on recent advancements in porphyrin-based MOFs,and highlighting their functionalized strategies and developments in diagnostic imaging and synergistic therapies.Finally,we proposed the challenges and prospects of these emerging materials in cancer theranostics.

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.

Aiming at early-stage vulnerable plaques:A nanoplatform with dual-mode imaging and lipid-inflammation integrated regulation for atherosclerotic theranostics

The vulnerable plaques in atherosclerosis can cause severe outcome with great danger of acute cardiovascular events.Thus,timely diagnosis and treatment of vulnerable plaques in early stage can effectively benefit the clinical management of atherosclerosis.In this work,a targeting theranostic strategy on early-stage vulnerable plaques in atherosclerosis is realized by a LAID nanoplatform with X-CT and fluorescent dual-mode imaging and lipid-inflammation integrated regulation abilities.The iodinated contrast agents(ICA),phenylboronic acid modified astaxanthin and oxidized-dextran(oxDEX)jointly construct the nanoparticles loaded with the lipid-specific probe LFP.LAID indicates an active targeting to plaques along with the dual-responsive disassembly in oxidative stress and acidic microenvironment of atherosclerosis.The X-CT signals of ICA execute the location of early-stage plaques,while the LFP combines with lipid cores and realizes the recognition of vulnerable plaques.Meanwhile,the treatment based on astaxanthin is performed for restraining the progression of plaques.Transcriptome sequencing suggests that LAID can inhibit the lipid uptake and block NF-κB pathway,which synergistically demonstrates a lipid-inflammation integrated regulation to suppression the plaques growing.The in vivo investigations suggest that LAID delivers a favorable theranostics to the early-stage vulnerable plaques,which provides an impressive prospect for reducing the adverse prognosis of atherosclerosis.

Photoluminescence and photothermal conversion in boric acid derived carbon dots for targeted microbial theranostics

Theranostic carbon dots(CDs)have attracted widespread attention recently due to their tunable optical properties and diverse bioactivities.Beyond fluorescent imaging application,the photothermal property endows CDs with the potential for microbial inactivation.However,realization of the effective conversion between fluorescence and heat in one CD system has rarely been reported.Herein,we provide a simple strategy for targeted microbial theranostics based on 4-carboxyphenylboronic acid-derived CDs(PCBA-CDs)which possess concentration-dependent photoluminescence/photothermal features.At lower concentrations,PCBA-CDs show bright and stable fluorescent signals ranging from blue to green.The fluorescence intensity gradually decreases with increasing concentration,while on the contrary,the photothermal effect of PCBA-CDs ascends progressively due to the rearrangement of electronic transitions in aggregated CDs.PCBA-CDs also demonstrate high affinity to the polysaccharide structures on the surface of microbe which allows rapid microbial fluorescence imaging as well as specific photothermal ablation of pathogens in skin wounds using PCBA-CDs at lower and higher concentrations,respectively.This study supplies a facile nanotheranostic strategy for just-in-time microbial management using bioactive CDs.

Harnessing the collective properties of nanoparticle ensembles for cancer theranostics

Individual inorganic nanoparticles （NPs） have been widely used in the fields of drug delivery, cancer imaging and therapy. There are still many hurdles that limit the performance of individual NPs for these applications. The utilization of highly ordered NP ensembles opens a door to resolve these problems, as a result of their new or advanced collective properties. The assembled NPs show several advantages over individual NP-based systems, such as improved cell internalization and tumor targeting, enhanced multimodality imaging capability, superior combination therapy arising from synergistic effects, possible complete clearance from the whole body by degradation of assemblies into original small NP building blocks, and so on. In this review, we discuss the potential of utilizing assembled NP ensembles for cancer imaging and treatment by taking plasmonic vesicular assemblies of Au NPs as an example. We first summarize the recent developments in the self-assembly of plasmonic vesicular structures of NPs from amphiphilic polymer-tethered NP building blocks. We further review the utilization of plasmonic vesicles of NPs for cancer imaging （e.g. multi-photon induced luminescence, photothermal, and photoacoustic imaging）, and cancer therapy （e.g., photothermal therapy, and chemotherapy）. Finally, we outline current challenges and our perspectives along this line.

Janus γ-Fe2O3/SiO2-based nanotheranostics for dual-modal imaging and enhanced synergistic cancer starvation/chemodynamic therapy

Multimodal cancer synergistic therapy exhibited remarkable advantages over monotherapy in producing an improved therapeutic efficacy. In this work, Janus-type γ-Fe2 O3/SiO2 nanoparticles(JFSNs) are conjugated with glucose oxidase(GOx) for synergistic cancer starvation/chemodynamic therapy. The γ-Fe2O3 hemisphere of JFSNs can perform photoacoustic/T2 magnetic resonance dual-modal imaging of tumors.GOx on the surface of JFSNs catalyzes the decomposition of glucose and produces H2O2 for cancer starvation therapy. Subsequently, the γ-Fe2O3 hemisphere catalyzes the disproportionation of H2O2 to generate highly reactive hydroxyl radicals in an acidic tumor microenvironment. The close distance between GOx and JFSNs ensures adequate contact between the γ-Fe2O3 hemisphere and its substrate H2O2, thus enhancing the catalytic efficiency. This synergy of glucose depletion, biotoxic H2O2 and hydroxyl radicals significantly suppresses 4 T1 mammary tumor growth with minimal adverse effects.

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.

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.

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.