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.

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.

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.

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.

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.

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.

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.

A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies.Heat shock protein 90(Hsp90)as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance.Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance.In this study,a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX,and a COAmodified 4-arm PEG polymer(4PSC)was synthesized.COA,an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression,was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity.Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity.By blocking the Hsp90 signaling pathway,4PSC significantly enhanced the antitumor effect of PTX,inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro.Remarkable results were further confirmed in vivo with two preclinical tumor models.These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.

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.

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.

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.

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.

Targeted and activatable nanosystem for fluorescent and optoacoustic imaging of immune-mediated inflammatory diseases and therapy via inhibiting NF-κB/NLRP3 pathways

Immune-mediated inflammatory diseases(IMIDs)represent a diverse group of diseases and challenges remain for the current medications.Herein,we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways.A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate(EGCG)through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety.BH-EGCG molecules readily form stable nanoparticles in aqueous medium,which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites.Additionally,an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&NAC@MM to further improve the anti-inflammatory efficacy.Benefiting from the inflammation-homing effect of the macrophage membrane,the nanosystem delivers payloads(diagnostic probe and therapeutic drugs)to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS,thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models,including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation.This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases.

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

Cancer is one of the most harmful diseases in the world, which causes huge numbers of deaths every year. Manydrugs have been developed to treat tumors. However, drug resistance usually develops after a period of time,which greatly weakens the therapeutic effect. Tumor drug resistance is characterized by blocking the action ofanticancer drugs, resisting apoptosis and DNA repair, and evading immune recognition. To tackle tumor drugresistance, many engineered drug delivery systems (DDS) have been developed. Metal-organic frameworks(MOFs) are one kind of emerging and promising nanocarriers for DDS with high surface area and abundant activesites that make the functionalization simpler and more efficient. These features enable MOFs to achieveadvantages easily towards other materials. In this review, we highlight the main mechanisms of tumor drugresistance and the characteristics of MOFs. The applications and opportunities of MOF-based DDS to overcometumor drug resistance are also discussed, shedding light on the future development of MOFs to address tumor drugresistance.

肿瘤微环境响应纳米体系用于提高肿瘤光免疫治疗

光免疫疗法在局部激光照射下杀伤肿瘤的同时,通过激活抗肿瘤免疫应答有效抑制肿瘤转移和复发。近些年,肿瘤微环境响应纳米体系(tumor-responsive nanosystems,TRNs)凭借在肿瘤部位通过选择性组装或解组装结构变构,实现治疗特性的精准可控,在肿瘤光学治疗和免疫治疗中受到广泛关注。为了深入剖析和阐明TRNs的结构控制与功能增强的构效机制,本文介绍了用于增强光免疫疗法的TRNs的设计构建、结构功能控制、肿瘤微环境重塑效用和相关机制。此外,笔者特别强调基于TRNs的光免疫疗法与免疫调节剂介导的免疫调节之间的协同机制。最后,笔者讨论了光免疫疗法这一新兴领域的挑战和未来前景。

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.

One-step reduction-encapsulated synthesis of Ag@polydopamine multicore-shell nanosystem for enhanced photoacoustic imaging and photothermal-chemodynamic cancer therapy

Though imaging-guided multimodal therapy has been demonstrated as an effective strategy to improve cancer diagnosis and therapy,challenge remains as to simplify the sophisticated synthesis procedure for the corresponding nanoagents.Herein,an insitu one-step reduction-encapsulated method has been reported,for the first time,to synthesize multicore-shell polydopaminecoated Ag nanoparticles(AgNPs@PDA)as a cancer theranostic agent,integrating amplified photoacoustic imaging,enhanced photothermal therapy,and photothermal promoted dual tumor microenvironment-coactivated chemodynamic therapy.The photoacoustic signal and the photothermal conversion efficiency of AgNPs@PDA nanosystem present a 6.6-and 4.2-fold enhancement compared to those of M-AgNPs-PDA(simply mixing PDA and AgNPs)derived from the increased interface heat transfer coefficient and the stronger near-infrared absorption.Importantly,AgNPs@PDA coactivated by dual tumor microenvironment(TME)enables controllable long-term release of hydroxyl radicals(·OH)and toxic Ag+,which can be further promoted by near-infrared light irradiation.Moreover,the high efficiency of AgNPs@PDA nanosystem with prominent photoacoustic imaging-guided synergistic photothermal-chemodynamic cancer treatment is also found in in vitro and in vivo studies.As a special mention,the formation mechanism of the one-step synthesized multicore-shell nanomaterials is systematically investigated.This work provides a much simplified one-step synthesis method for the construction of a versatile nanoplatform for cancer theranostics with high efficacy.

Cisplatin and paclitaxel co-delivery nanosystem for ovarian cancer chemotherapy

We have designed and developed an effective drug delivery system using biocompatible polymer of poly(ethylene glycol)-polyaspartic acid(mPEG-PAsp)for co-loading the chemotherapy drugs paclitaxel(PTX)and cisplatin(CP)in one nano-vehicle.This study aimed to improve the anti-cancer effi-cacy of combinations of chemotherapy drugs and reduce their side effects.mPEG-PAsp-(PTX/Pt)nano-micelles disperse well in aqueous solution and have a narrow size distribution(37.863.2 nm)in dynamic light scattering(DLS).Drug release profiles found that CP released at pH 5.5 was signifi-cantly faster than that at pH 7.4.MPEG-PAsp-(PTX/Pt)nano-micelles displayed a significantly higher tumor inhibitory effect than mPEG-PAsp-PTX nano-micelles when the polymer concentrations reached 50 lg/mL.Our data indicated that polymer micelles of mPEG-PAsp loaded with the combined drug exert synergistic anti-tumor efficacy on SKOV3 ovarian cells via different action mechanisms.Results from our studies suggested that mPEG-PAsp-(PTX/Pt)nano-micelles are promising alternatives for carrying and improving the delivery of therapeutic drugs with different water solubilities.

纳米抗菌药物治疗胞内菌感染的研究进展

胞内菌通过在宿主细胞内生存以逃避机体免疫系统的监视,宿主细胞的膜屏障作用致使抗菌药物无法进入胞内杀灭细菌,这使得胞内菌感染成为一大治疗难题。纳米药物的独特结构促使其能有效跨细胞转运并逃逸溶酶体降解,因此所荷载的抗菌药物能在胞内维持有效浓度,实现胞内菌感染的高效治疗。此外,许多纳米材料自身也具备独特的抗菌特性。本文将对纳米药物治疗胞内菌感染的药效学及机制进行总结概述,以期为抗胞内菌纳米药物的研发提供借鉴,并为解决胞内菌感染的治疗难题提供新方案。