Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Combination therapy to overcome ferroptosis resistance by biomimetic self-assembly nano-prodrug

Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer.Herein,we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib(Gefi),ferrocene(Fc)and dihydroartemisinin(DHA)for the combined therapy of both ferroptosis and apoptosis.In the tumor microenvironment,this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH.Interestingly,the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc,further executing tumor cell death with concomitant chemotherapy by Gefi.More importantly,this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis,as well as no noticeable side-effects during treatments.This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.

Study on the Modification of Nanodiamond with DN-IO

Fourier transform infrared spectroscopy （FT-IR） and ζ-potential were introduced to study the effect of different modification parameters on the surface properties of nanodiamond （ND）. Results showed that under stirring grinding grinding conditions, ND hard aggregates were smashed and some active spots on them reacted with surfactant molecules, which led to the increase in its ζ-potential and stability. Different models of surface modification were also given in this study.

从SoC到SDSoW:微电子发展的新范式

微电子在智能时代正迎来新一轮技术与产业的重大变革期.本文从智能时代的科学方法论、系统集成的工程技术路线和微电子摩尔定律(Moore’s law)的维度扩展3个层面导入,提出了网络极大化节点极小化的复杂巨系统构造、异构异质芯粒的晶上拼装集成、硬件资源的领域专用软硬件协同定义,形成了软件定义晶上系统的新发展范式,对微电子的设计方法、系统集成、应用开发、经济性指标等进行了内涵升级,可全面刷新信息基础设施的技术物理形态,贡献一条“晶圆级硅基直连”的系统集成工程技术路线,并有望打造出智能涌现的物理底座.

Remote-controlled dexamethasone-duration on eye-surface with a micelle-magnetic nanoparticulate co-delivery system for dry eye disease

Dexamethasone(DEX)is used to treat ocular surface diseases.However,regulating DEX duration in tears while preventing its absorption into the anterior chamber is critical for balancing its therapy effects and the side effects.In this study,a novel magnetic nanoparticle(MNP)-micelle(MC)codelivery system(MMDS)was developed.The MC moiety in the MMDS served as the carrier for DEX and the MNP part endowed the MMDS with magnetic-responsive properties.To extend its residency,the MMDS was magnetically attracted by an external magnet after instilling,which acted as a precorneal drug-depot enabling a sustainable release of DEX in tears.With combination of magnet treatment,the topical instillation of MMDS@DEX significantly prolonged the DEX-retention in tears and increased the DEX-concentration in the cornea and conjunctiva,as well as concurrently reduced the DEX-level in the aqueous humor,when compared with the commercial DEX eye drop treatment.The combination of MMDS@DEX and magnet treatment exerted significantly better therapeutic effects against DED with smaller side effects than conventional treatments including DEX suspension,commercial DEX eye drops,as well as the MMDS@DEX treatment alone.The present work provided a new method for the effective delivery of DEX to ocular surface tissues while reducing its side effects,which will be beneficial to the treatments of a wide range of ocular surface diseases.

Mitochondrial metabolism blockade nanoadjuvant reversed immune-resistance microenvironment to sensitize albumin-bound paclitaxel-based chemo-immunotherapy

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps,we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembledwith albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors, further supporting its better clinical application。

ROS-degradable polythioketal urethane scaffold for porcine wound repair

Porous,resorbable synthetic biomaterials such as polyesters provide a cost-effective framework for the healing of skin wounds.However,it must be optimized to reduce acidic breakdown and improve immunological and regenerative responses.Recently,Craig L.Duvall^(1) and his team published his work in Science Translational Medicine,which delineates the synthesis,characterization,and application of ethylene glycol(EG7)polythioketal urethane(PTK-UR).Here,they integrate seven ethylene glycol repeats unites in the PTK-UR polymer backbone to enhance its hydrophilicity and biological compatibility,facilitating optimal wound-healing processes in porcine skin models.These implants promote extracellular matrix(ECM)deposition,reepithelialization,and remodeling while effectively transitioning to a healing phenotype from a moderate inflammatory response.

De novo design of highly efficient type-Ⅰphotosensitizer based onπ-conjugated oligomer for photodynamic eradication of multidrug-resistant bacterial infections

Traditional photosensitizers show limited singlet oxygen generation in hypoxic infection lesions,which greatly suppress their performance in antibacterial therapy.Meanwhile,there still is lack of feasible design strategy for developing hypoxia-overcoming photosensitizers agents.Herein,radical generation ofπ-conjugated small molecules is efficiently manipulated by an individual selenium(Se)substituent.With this strategy,the first proof-of-concept study of a Se-anchored oligo(thienyl ethynylene)(OT-Se)with high-performance superoxide radical(O_(2)^(·-))and hydroxyl radical(·OH)generation capability is present,and achieves efficient antibacterial activities towards the clinically extracted multidrug-resistant bacteria methicillin-resistant S.aureus(MRSA)and carbapenem-resistant E.coli(CREC)at sub-micromolar concentration under a low white light irradiation(30 mW/cm^(2)).The water-dispersible OT-Se shows a good bacteria-anchoring capability,biocompatibility,and complete elimination of multidrug-resistant bacteria wound infection in vivo.This work offers a strategy to boost type-I photodynamic therapy(PDT)performance for efficient antibacterial treatments,advancing the development of antibacterial agents.

Author correction to“Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy”[Acta Pharm Sin B(2022)4204-4223]

The authors regret that there are errors in the article Fig.8A and Fig.S22A due to the mistake of copying and pasting in the process of assembling figures and negligence in the proofreading.Although it does not affect the conclusion,these are obvious errors.The authors have now modified as below.The original data of these figures have been provided to the Editorial Office,and the corresponding authors or the Editorial Office can be contacted for original data access.The authors apologize for any inconvenience caused to the journal and readers.

Author correction to‘Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics’[Acta Pharm Sin B 12(2022)4458–4471]

The authors regret that there is an error in Fig.6 in the article due to the mistake of copying and pasting in the process of assemblingfigures and negligence in the proofreading.Although it does not affect the conclusion,it is an obvious error.The authors have now modified as below.The authors apologize for any inconvenience caused to the journal and readers.

Recent advances in access to overcome cancer drug resistance by nanocarrier drug delivery system

Cancer is currently one of the most intractable diseases causing human death.Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods,multidrug resistance(MDR)of tumor cells is still a major problem leading to clinical treatment failure.Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug,usually inherent or developed during treatment.Therefore,an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy.The rapid development of nanotechnology has brought us new enlightenments to solve this problem.The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance,high toxicity,lack of targeting,and off-target.Herein,we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance.Nanomaterials contain liposomes,polymer conjugates,micelles,dendrimers,carbon-based,metal nanoparticles,and nucleotides which can be used to deliver chemotherapeutic drugs,photosensitizers,and small interfering RNA(siRNA).This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.

A highly selective fluorescent probe for visualizing dry eye disease-associated viscosity variations

Dry eye disease(DED) is a multifactorial chronic inflammatory disease of the ocular surface with complex and unclear etiology. The development of reliable detection tools for the pathology of DED will benefit its treatment, but it is still lacking. In parallel, it has been discovered recently that viscosity changes are involved in inflammation processes. In this regard, we constructed a fluorescent probe V5with an asymmetric donor-acceptor-donor(D-A-D) feature after rational structural modulation for viscosity detection during DED progression. The probe manifested a remarkable fluorescence enhancement(110 folds) in highly viscous conditions without interferences from polarity and reactive species. Specifically, no aggregation effect of the probe was found in glycerol. Moreover, viscosity increment in human corneal epithelial cells(HCECs) induced by hyperosmosis and inflammation was monitored, and ferroptosis in HCECs also led to the viscosity elevation. A reactive oxygen species(ROS)-dependent viscosity changes during DED progression is demonstrated. Finally, viscosity change in corneal epithelial cell layer from mice treated by scopolamine was also visualized for the first time. We anticipate this work can provide a new lens to the pathogenesis study and diagnosis of DED and other ophthalmic diseases using fluorescence methods.

Solvent-mediated handedness inversed and amplified circularly polarized luminescence system based on camptothecin derivative

To realize the handedness controllable circularly polarized luminescence(CPL) system remains challenging. Herein, the solvent-mediated CPL inversion and amplification systems were successfully constructed by camptothecin derivative(CPT-A). Due to the planar structure of N,N-dimethylformamide, it could coassemble with CPT-A, resulting in the alteration of g_(lum) from –0.0082 to +0.0085 by increasing water content. While in the non-planar solvent(hexafluoroisopropanol), the g_(lum) was amplified to 0.034 with the increase in water content. Moreover, the CPT-A could react with the glutathione, resulting in the anticancer drug CPT to make it more toxic to the cancer cells. Overall, the handedness controllable CPL systems were realized by tuning the supramolecular self-assembly of a prodrug.

计算体系架构研究综述与思考

随着摩尔定律(Moore's law)与迪纳德(Dennard)缩放定律逐步走向终结,依靠集成电路制程工艺的进步提升计算系统性能与效能越来越困难,计算体系架构的演进成为了未来计算系统发展的重要技术途径.本文首先从应用适应性、计算驱动方式、系统重心变化、计算核心构成,以及计算逻辑使用等不同的角度回顾了体系架构的发展历程,总结了不同体系架构的优缺点;然后着重分析了在人工智能、大数据等应用飞速发展的条件下未来计算系统的能力需求特征;最后提出了软件定义计算体系架构,并梳理了其重点研究内容与关键技术,为未来计算体系架构的发展提供了一条可行的技术途径.

Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering

Polysaccharide hydrogels are widely used in tissue engineering because of their superior biocompatibility and low immunogenicity.However,many of these hydrogels are unrealistic for practical applications as the cost of raw materials is high,and the fabrication steps are tedious.This study focuses on the facile fabrication and optimization of agarose-polydopamine hydrogel(APG)scaffolds for skin wound healing.The first study objective was to evaluate the effects of polydopamine(PDA)on the mechanical properties,water holding capacity and cell adhesiveness of APG.We observed that APG showed decreased rigidity and increased water content with the addition of PDA.Most importantly,decreased rigidity translated into significant increase in cell adhesiveness.Next,the slow biodegradability and high biocompatibility of APG with the highest PDA content(APG3)was confirmed.In addition,APG3 promoted full-thickness skin defect healing by accelerating collagen deposition and promoting angiogenesis.Altogether,we have developed a straightforward and efficient strategy to construct functional APG scaffold for skin tissue engineering,which has translation potentials in clinical practice.

Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics

Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis process mediated by caspase-1,is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.To address these issues,hexahistidine(His6)-metal assembly(HmA)was employed as the drug delivery vector to load nigericin(Nig)and decitabine(DAC)affording a dual-drug delivery system(Nig^(+)DAC)@HmA.The(Nig^(+)DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis,easily escape from the lysosome,and are highly distributed in the tumor sites.DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome and caspase-1 protein activated by Nig.Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.Our results suggest that such an easy-to-manipulate self-assembled nano-system(Nig^(+)DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation.

Polydopamine nanoparticle-dotted food gum hydrogel with excellent antibacterial activity and rapid shape adaptability for accelerated bacteria-infected wound healing

Most commonly used wound dressings have severe problems,such as an inability to adapt to wound shape or a lack of antibacterial capacity,affecting their ability to meet the requirements of clinical applications.Here,a nanocomposite hydrogel(XKP)is developed by introducing polydopamine nanoparticles(PDA NPs)into a food gum matrix(XK,consisting of xanthan gum and konjac glucomannan,both FDA-approved food thickening agents)for skin wound healing.In this system,the embedded PDA NPs not only interact with the food gum matrix to form a hydrogel with excellent mechanical strength,but also act as photothermal transduction agents to convert near-infrared laser radiation to heat,thereby triggering bacterial death.Moreover,the XKP hydrogel has high elasticity and tunable water content,enabling it to adapt to the shape of the wound and insulate it,providing a moist environment suitable for healing.In-vivo skin wound healing results clearly demonstrate that XKP can significantly accelerate the healing of wounds by reducing the inflammatory response and promoting vascular reconstruction.In summary,this strategy provides a simple and practical method to overcome the drawbacks of traditional wound dressings,and provides further options when choosing suitable wound healing materials for clinical applications.

Effects of total parenteral nutrition on drug metabolism gene expression in mice

Parenteral nutrition-associated liver disease(PNALD)is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition(TPN).Omega-6 rich Intralipid?and omega-3 rich Omegaven?are two intravenous lipid emulsions used in TPN.TPN could affect the hepatic expression of genes in anti-oxidative stress,but it’s unknown whether TPN affects genes in drug metabolism.In this study,either Intralipid?-or Omegaven?-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed,glutathione(GSH)levels were measured,and protein levels for two key drug metabolism geneswere determined.Overall,the expression of most genes was downregulated by Intralipid?-based TPN(Gstpl,Gstml,3,6,Nqol,Ho-1,Mt-1,Gclc,Gclm,Cyp2d9,2f2,2b 10,and 3a11).Omegaven?showed similar results as Intralipid?except for preserving the expression of Gstml and Cyp3a11,and increasing Ho-1.Total GSH levels were decreased by Intralipid?,but increased by Omegaven?.CYP3A11 protein levels were increased by Omegaven?.In conclusion,TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice.However,Omegaven?preserved expression of Cyp3a11,suggesting another beneficial effect of Omegaven?in protecting liver functions.

Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy

As a promising modality for cancer therapy, photodynamic therapy(PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin(BSA-MHI148) and multi-kinase inhibitor Sorafenib(SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms:(i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory.(ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows:(i) Enhanced immunogenic cell death(ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species(ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability.(ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSAMHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.

Electrochemiluminescence sensing platform for microorganism detection

Electrobiochemiluminescence(ECL)is a type of luminescence in which substances produced on electrode undergoes an electron transition to an excited state for light-emitting[1].As a sensing platform,ECL instruments have been widely used in clinical diagnosis,environmental monitoring,food and water safety,biological defense and other fields benefiting from their low detection limits,extensive dynamic range,fast detection speed,and low instrument cost.In this perspective,we highlight some representative examples of microbial detection by ECL sensing platforms in biosafety and health applications.