Correction:Nanomaterial-Based Repurposing of Macrophage Metabolism and Its Applications

Following publication of the original article[1],the authors reported an error in the last author’s name,it was mistakenly written as“Jun Den”.The correct author’s name“Jun Deng”has been updated in this Correction.

Nanomaterial‑Based Repurposing of Macrophage Metabolism and Its Applications

Macrophage immunotherapy represents an emerging therapeutic approach aimed at modulating the immune response to alleviate disease symptoms.Nanomaterials(NMs)have been engineered to monitor macrophage metabolism,enabling the evaluation of disease progression and the replication of intricate physiological signal patterns.They achieve this either directly or by delivering regulatory signals,thereby mapping phenotype to effector functions through metabolic repurposing to customize macrophage fate for therapy.However,a comprehensive summary regarding NM-mediated macrophage visualization and coordinated metabolic rewiring to maintain phenotypic equilibrium is currently lacking.This review aims to address this gap by outlining recent advancements in NM-based metabolic immunotherapy.We initially explore the relationship between metabolism,polarization,and disease,before delving into recent NM innovations that visualize macrophage activity to elucidate disease onset and fine-tune its fate through metabolic remodeling for macrophage-centered immunotherapy.Finally,we discuss the prospects and challenges of NM-mediated metabolic immunotherapy,aiming to accelerate clinical translation.We anticipate that this review will serve as a valuable reference for researchers seeking to leverage novel metabolic intervention-matched immunomodulators in macrophages or other fields of immune engineering.

制备用于间充质干细胞成像的荧光成像/磁共振成像/正电子发射断层扫描三模态纳米探针

为了在间充质干细胞移植的各个阶段更好地获取移植干细胞的命运信息,制备了一种能同时实现荧光成像(FI)、磁共振成像(MRI)和正电子发射断层扫描(PET)的影像探针。首先制备了一种新型两亲性嵌段共聚物,第1嵌段为叔丁氧羰基保护的2-((叔丁氧羰基)氨基)丙烯酸乙酯的均聚物,第2嵌段为短链聚乙二醇丙烯酸酯和五氟苯酚丙烯酸酯的无规共聚物,再通过氨解和酰胺化反应为聚合物修饰上双功能螯合剂DOTA和近红外染料Cy5.5,通过核磁共振和凝胶渗透色谱对聚合物结构及相对分子质量进行了表征和分析。聚合物在水中自组装并螯合Gd^(3+)得到1 mg/mL的纳米探针Gd-DOTA-Cy5.5-NP,动态光散射和透射电镜观察到探针为平均粒径30 nm的球形颗粒,并用电感耦合等离子体光谱法测得Gd^(3+)浓度为0.084 mmol/L。将纳米探针与间充质干细胞共孵育,通过Cell Counting Kit-8试剂验证1 mg/mL以下的Gd-DOTA-Cy5.5-NP相对细胞毒性较低,同时激光共聚焦显微镜在675 nm激发波长下观测细胞出现红色荧光,利用3.0 T磁共振成像系统测得探针纵向弛豫率为46.969 mmol/(L·s)。最后Gd-DOTA-Cy5.5-NP螯合^(68)Ga^(3+),得到三模态纳米探针^(68)Ga/Gd-DOTA-Cy5.5-NP,伽马计数仪测得间充质干细胞对该探针的摄取在90 min达到饱和。

Key progresses of MOE key laboratory of macromolecular synthesis and functionalization in 2022

In 2022,The MOE Key Laboratory of Macromolecular Synthesis and Functionalization in Zhejiang University had achieved several important results.First,a series of well-defined dinuclear organoboron catalysts were developed to precisely control the enchainment of ether and carbonate segments during the copolymerization of CO_(2)and epoxides.Second,polyester had been synthesized through cationic copolymerization of cyclic anhydride.Third,ring-opening polymerization of carbon dioxide based valerolactone had been achieved,revealing the prospect of 3-ethylidene-6-vinyltetrahydro-2H-pyran-2-one(EVL)in utilizing CO_(2)and synthesizing functional polymers.Fourth,machine learning methods have been applied to biomaterial research,enabling high-throughput screening of functional biomaterial surfaces for implantable devices,and searching for potent antimicrobial peptides in whole combinatorial peptide libraries.Fifth,methods of characterization of biomacromolecule RNA transcription and manipulation of nucleoside modification were developed.Sixth,artificial enzymes-armed Bifidobacterium Longum probiotics were established to tune down gut inflammation.Seventh,three-dimensional(3D)printing technologies were used to engineer tough supramolecular hydrogels.Eighth,hydroplastic foaming graphene frameworks for acoustic and conductive polymer composites were provided for application.Ninth,aggregate photophysics about the nature of through-space interactions(TSIs)and manipulating their strength in small molecules with non-conjugated structure had been elucidated.Tenth,the forming mechanism of a newfound nested texture in poly(L-lactic acid)(PLLA)spherulitic films had been revealed.Finally,the isotropically dyeing mechanism of KDP single crystals grown from hydrogels have been explored.The related works are reviewed in this paper.

Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport.For their clinical application,nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects.Therefore,responsive drug-release strategies for inflammation treatment have been explored;however,no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation.Herein,we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes(R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate,RC-NL@DMF)that pre-cisely release encapsulated anti-pyroptotic drugs into pyroptotic cells.The activated key pyroptotic protein,the N-terminal domain of gasdermin E,selectively integrates with the cardiolipin of liposomes,thus forming pores for controlled drug release,pyroptosis,and inflammation inhibition.Therefore,RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice.Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery,suppressing pyroptosis and treating autoimmune inflammatory diseases.

Bioactive Hydrogels with Pro-coagulation Effect for Hemostasis

Hemostatic hydrogels are widely applied for wound management of damaged tissues,traumatic wounds,and surgical incisions.Some hydrogels composed of bioactive components,including fibrin and thrombin,showed great promise in the clinic due to their good pro-coagulation effect.With the expanding knowledge of cascade reaction of blood coagulation and emerging bioactive substances,massive bioactive hydrogels consisting of peptides,hemocoagulase,polyphosphate(polyP),etc.,have been developed as effective hemostatic materials.Based on the coagulation process and mechanism,we summarize the role of reported bioactive hydrogels in hemostasis in this review.We conclude the key points in the coagulation process,including activation of coagulation factors,fibrinogen polymerization,etc.,then discuss how to design bioactive hydrogels to accelerate coagulation targeted to these points.Finally,we conclude the progress and propose a perspective of bioactive hydrogels with a pro-coagulation effect for hemostasis.

C176-loaded and phosphatidylserine-modified nanoparticles treat retinal neovascularization by promoting M2 macrophage polarization

Retinal neovascularization(RNV),a typical pathological manifestation involved in most neovascular diseases,causes retinal detachment,vision loss,and ultimately irreversible blindness.Repeated intravitreal injections of anti-VEGF drugs were developed against RNV,with limitations of incomplete responses and adverse effects.Therefore,a new treatment with a better curative effect and more prolonged dosage is demanding.Here,we induced macrophage polarization to anti-inflammatory M2 phenotype by inhibiting cGAS-STING signaling with an antagonist C176,appreciating the role of cGAS-STING signaling in the retina in pro-inflammatory M1 polarization.C176-loaded and phosphatidylserine-modified dendritic mesoporous silica nanoparticles were constructed and examined by a single intravitreal injection.The biosafe nanoparticles were phagocytosed by retinal macrophages through a phosphatidylserine-mediated“eat me”signal,which persistently release C176 to suppress STING signaling and thereby promote macrophage M2 polarization specifically.A single dosage can effectively alleviate pathological angiogenesis phenotypes in murine oxygen-induced retinopathy models.In conclusion,these C176-loaded nanoparticles with enhanced cell uptake and long-lasting STING inhibition effects might serve as a promising way for treating RNV.

Adaptable hydrogel with reversible linkages for regenerative medicine:Dynamic mechanical microenvironment for cells

Hydrogels are three-dimensional platforms that serve as substitutes for native extracellular matrix.These materials are starting to play important roles in regenerative medicine because of their similarities to native matrix in water content and flexibility.It would be very advantagoues for researchers to be able to regulate cell behavior and fate with specific hydrogels that have tunable mechanical properties as biophysical cues.Recent developments in dynamic chemistry have yielded designs of adaptable hydrogels that mimic dynamic nature of extracellular matrix.The current review provides a comprehensive overview for adaptable hydrogel in regenerative medicine as follows.First,we outline strategies to design adaptable hydrogel network with reversible linkages according to previous findings in supramolecular chemistry and dynamic covalent chemistry.Next,we describe the mechanism of dynamic mechanical microenvironment influence cell behaviors and fate,including how stress relaxation influences on cell behavior and how mechanosignals regulate matrix remodeling.Finally,we highlight techniques such as bioprinting which utilize adaptable hydrogel in regenerative medicine.We conclude by discussing the limitations and challenges for adaptable hydrogel,and we present perspectives for future studies.

Construction of heparin-based hydrogel incorporated with Cu_(5.4)O ultrasmall nanozymes for wound healing and inflammation inhibition

Excessive production of inflammatory chemokines and reactive oxygen species(ROS)can cause a feedback cycle of inflammation response that has a negative effect on cutaneous wound healing.The use of wound-dressing materials that simultaneously absorb chemokines and scavenge ROS constitutes a novel‘weeding and uprooting’treatment strategy for inflammatory conditions.In the present study,a composite hydrogel comprising an amine-functionalized star-shaped polyethylene glycol(starPEG)and heparin for chemokine sequestration as well as Cu_(5.4)O ultrasmall nanozymes for ROS scavenging(Cu_(5.4)O@Hep-PEG)was developed.The material effectively adsorbs the inflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8,decreasing the migratory activity of macrophages and neutrophils.Furthermore,it scavenges the ROS in wound fluids to mitigate oxidative stress,and the sustained release of Cu_(5.4)O promotes angiogenesis.In acute wounds and impaired-healing wounds(diabetic wounds),Cu_(5.4)O@Hep-PEG hydrogels outperform the standard-of-care product Promogram®in terms of inflammation reduction,increased epidermis regeneration,vascularization,and wound closure.

ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation

Ischemic stroke is an acute and serious cerebral vascular disease,which greatly affects people’s health and brings huge economic burden to society.Microglia,as important innate immune components in central nervous system(CNS),are double-edged swords in the battle of nerve injury,considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes.High mobility group box 1(HMGB1)is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia.18β-glycyrrhetinic acid(GA)is an effective intracellular inhibitor of HMGB1,but of poor water solubility and dose-dependent toxicity.To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy,herein,we designed reactive oxygen species(ROS)responsive polymer-drug conjugate nanoparticles(DGA)to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1.DGA presented excellent therapeutic efficacy in stroke mice,as evidenced by the reduction of infarct volume,recovery of motor function,suppressed of M1 microglia activation and enhanced M2 activation,and induction of neurogenesis.Altogether,our work demonstrates a close association between HMGB1 and microglia polarization,suggesting potential strategies for coping with inflammatory microglia-related diseases.

C-176 loaded Ce DNase nanoparticles synergistically inhibit the cGAS-STING pathway for ischemic stroke treatment

The neuroinflammatory responses following ischemic stroke cause irreversible nerve cell death.Cell free-double strand DNA(dsDNA)segments from ischemic tissue debris are engulfed by microglia and sensed by their cyclic GMP-AMP synthase(cGAS),which triggers robust activation of the innate immune stimulator of interferon genes(STING)pathway and initiate the chronic inflammatory cascade.The decomposition of immunogenic dsDNA and inhibition of the innate immune STING are synergistic immunologic targets for ameliorating neuroinflammation.To combine the anti-inflammatory strategies of STING inhibition and dsDNA elimination,we constructed a DNase-mimetic artificial enzyme loaded with C-176.Nanoparticles are self-assembled by amphiphilic copolymers(P[CL35-b-(OEGMA20.7-co-NTAMA14.3)]),C-176,and Ce^(4+)which is coordinated with nitrilotriacetic acid(NTA)group to form corresponding catalytic structures.Our work developed a new nano-drug that balances the cGAS-STING axis to enhance the therapeutic impact of stroke by combining the DNase-memetic Ce^(4+)enzyme and STING inhibitor synergistically.In conclusion,it is a novel approach to modulating central nervus system(CNS)inflammatory signaling pathways and improving stroke prognosis.

Synergistically targeting synovium STING pathway for rheumatoid arthritis treatment

Rheumatoid arthritis(RA)is a common autoimmune disease leading to pain,disability,and even death.Although studies have revealed that aberrant activation of STING was implicated in various autoimmune diseases,the role of STING in RA remains unclear.In the current study,we demonstrated that STING activation was pivotal in RA pathogenesis.As the accumulation of dsDNA,a specific stimulus for STING,is a feature of RA,we developed a spherical polyethyleneimine-coated mesoporous polydopamine nanoparticles loaded with STING antagonist C-176(PEI-PDA@C-176 NPs)for treating RA.The fabricated NPs with biocompatibility had high DNA adsorption ability and could effectively inhibit the STING pathway and inflammation in macrophages.Intra-articular administration of PEI-PDA@C-176 NPs could effectively reduce joint damage in mice models of dsDNA-induced arthritis and collagen-induced arthritis by inhibiting STING pathway.We concluded that materials with synergistic effects of STING inhibition might be an efficacious strategy to treat RA.

Doxorubicin-conjugated pH-responsive gold nanorods for combined photothermal therapy and chemotherapy of cancer

Cancer chemotherapy can be hindered by drug resistance which leads to lower drug efficiency.Here,we have developed a drug delivery system that tethers doxorubicin to the surface of gold nanorods via a pHsensitive linkage(AuNRs@DOX),for a combined photothermal and chemical therapy for cancer.First,AuNRs@DOX is ingested by HepG2 liver cancer cells.After endocytosis,the acidic pH triggers the release of doxorubicin,which leads to chemotherapeutic effects.The gold nanorods are not only carriers of DOX,but also photothermal conversion agents.In the presence of an 808 nm near-infrared laser,AuNRs@DOX significantly enhance the cytotoxicity of doxorubicin via the photothermal effect,which induces elevated apoptosis of hepG2 cancer cells,leading to better therapeutic effects in vitro and in vivo.

Adsorption of plasma proteins and fibronectin on poly(hydroxylethyl methacrylate) brushes of different thickness and their relationship with adhesion and migration of vascular smooth muscle cells

The surface-grafted poly(hydroxylethyl methacrylate)(PHEMA)molecules were demonstrated to show a brush state regardless of their molecular length(molecular weight).Adsorption of proteins from 10%fetal bovine serum(FBS),fibronectin(Fn)and bovine serum albumin(BSA)was quantified by ellipsometry,revealing that the amounts of FBS and Fn decreased monotonously along with the increase of PHEMA thickness,whereas not detectable for BSA when the PHEMA thickness was larger than 6 nm.Radio immunoassay found that the adsorption of Fn from 10%FBS had no significant difference regardless of the PHEMA thickness.However,ELISA results showed that the Arg-Gly-Asp(RGD)activity of adsorbed Fn decreased with the increase of PHEMA thickness.By comparison of cellular behaviors of vascular smooth muscle cells(VSMCs)being cultured in vitro in the normal serum-containing medium and the Fn-depleted serum-containing medium,the significant role of Fn on modulating the adhesion and migration of VSMCs was verified.Taking account all the results,the Fn adsorption model and its role on linking the biomaterials surface to the VSMCs behaviors are proposed.

Trilayered Fibrous Dressing with Wettability Gradient for Spontaneous and Directional Transport of Massive Exudate and Wound Healing Promotion

Excessive exudate at wound sites increases treatment difficulty and severely decelerates the healing process.In wound exu-date management,dressings with unidirectional liquid transport capability have exhibited enormous potential.However,it remains challenging to improve the one-way liquid transport efficiency.Herein,a trilayered fibrous dressing is constructed by sequentially electrospinning polyurethane(PU)and polyvinylidene fluoride(PVDF)onto cotton fabric.Through hot pressing,a stable wettability gradient is formed across the PVDF/PU/cotton dressing due to the melting and bridging of PU nanofib-ers.The trilayered dressing exhibited rapid unidirectional transport with water penetrating from the hydrophobic side to the hydrophilic side in 6 s.The hydrostatic pressure from the hydrophilic side to the hydrophobic side is 569%higher than that from the hydrophobic side to the hydrophilic side,indicating that the dressing has a profound unidirectional conductivity.In vivo experiments demonstrates that the trilayered dressing can accelerate the wound healing process,especially in the early stages of wound occurrence,by quickly draining the excessive exudate.This study provides a new method to construct wound dressings with wettability gradients,which are advantageous for efficient exudate removal.

Implantable Thermal Therapeutic Device with Precise Temperature Control Enabled by Foldable Electronics and Heat-Insulating Pads

Thermal therapy has continued to attract the attention of researchers and clinicians due to its important applications in tumor ablation,wound management,and drug release.The lack of precise temperature control capability in traditional thermal treatment may cause the decrease of therapeutic effect and thermal damage to normal tissues.Here,we report an implantable thermal therapeutic device(ITTD),which offers precise closed loop heating,in situ temperature monitoring,and thermal protection.The ITTD features a multifunctional foldable electronics device wrapped on a heat-insulating composite pad.Experimental and numerical studies reveal the fundamental aspects of the design,fabrication,and operation of the ITTD.In vivo experiments of the ITTD in thermal ablation for antitumor demonstrate that the proposed ITTD is capable of controlling the ablation temperature precisely in real time with a precision of at least 0.7℃ and providing effective thermal protection to normal tissues.This proof-of-concept research creates a promising route to develop ITTD with precise temperature control capability,which is highly desired in thermal therapy and other disease diagnosis and treatments.

Key progresses of MOE key laboratory of macromolecular synthesis and functionalization in 2023

In 2023,The MOE Key Laboratory of Macromolecular Synthesis and Functionalization in Zhejiang University had achieved several important results in the five research directions.First,for controllable catalytic polymerization,a new silicon-centered organoboron binary catalyst was developed for copolymerization of epoxides,and a series of cooperative organocatalysts were proposed for ring-opening copolymerization of chalcogen-rich monomers.Second,with respect to microstructure and rheology,axially encoded metafiber demonstrated its capacity for integrating multiple electronics,while artificial nacre materials showed improved strength and toughness due to interlayer entanglement.Third,concerning separating functional polymers,interfacial polymerization was monitored via aggregation-induced emission,and vacuum filtration was applied to assist interfacial polymerization.Fourth,in terms of biomedical functional polymers,we designed antibacterial materials such as a novel quaternary ammonium salt that enables polyethylene terephthalate recycling and its antibacterial function,nanozyme-armed phage proved its efficiency in combating bacterial infection,and also transition metal nanoparticles showed capacities in antibacterial treatments.We also made achievements in biomedical materials,including polymeric microneedles for minimally invasive implantation and functionalization of cardiac patches,as well as ROSresponsive/scavenging prodrug/miRNA balloon coating to promote drug delivery efficiency.Besides,methods and mechanisms of RNA labeling has been developed.Fifth,about photo-electro-magnetic functional polymers,through-space conjugation was successfully manipulated by altering subunit packing modes,room-temperature phosphorescent hydrogels were synthesized via polymerization-induced crystallization of dopant molecules,and single crystals of both fullerene and non-fullerene acceptors were grown in crystallized organogel,with their photodetection performance further explored.The related works are reviewed in this paper.