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Mn-based cGAS-STING activation for tumor therapy

Chinese Journal of Cancer Research 2023年第1期35卷 19-43页

作者： Aiping Huang Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Changsha Medical University Academician WorkstationChangsha 410219China

Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases.However,the overall responsive rate of current immunotherapy is still unsatisfactory,benefiting only a small proportion of patients.Therefore,significant attention has been paid to the modulation of tumor microenvironment(TME)for the enhancement of immunotherapy.Interestingly,recent studies have shown that cyclic GMP-AMP synthasestimulator of interferon gene(cGAS-STING)was initially found as an innate immune sensor to recognize cytoplasmic DNA(such as bacterial,viral,micronuclei,and mitochondrial).It is a promising signaling pathway to activate antitumor immune responses via type I interferon production.Notably,Mn^(2+)was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better immunotherapy.This activation led to the development of Mn^(2+)-based strategies for tumor immunotherapy via the activation of the cGAS-STING pathway.In this critical review,we aimed to summarize the recent progress of this field,focusing on the following three aspects.First,we briefly introduced the signaling pathway of cGAS-STING activation,and its regulation effect on the antitumor immunity cycle has been discussed.Along with this,several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic drugs.Then,the basic biological functions of Mn^(2+)have been illustrated,focusing on its critical roles in the cGAS-STING pathway activation.Next,we systematically reviewed the Mn^(2+)-based strategies for tumor immunotherapy,which can be classified by the methods based on Mn^(2+)alone or Mn^(2+)combined with other therapeutic modalities.We finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn^(2+)-based therapeutics.

关键词： Tumor immunity metal ions combinatorial therapy targeting nanoparticles

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Harnessing bacteria for tumor therapy:Current advances and challenges

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Chinese Chemical Letters 2024年第2期35卷 97-106页

作者： Lina Guo Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Changsha Medical University Academician WorkstationChangsha 410219China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410008China

After a century of standstill,bacteria-based tumor therapy has resurged recently benefiting from the revolution of tumor immunotherapy,which provides unique solutions to tackle the obstacles of traditional tumor treatments.Obligate and facultative anaerobes with active tropism can selectively colonize at tumor sites and suppress tumor growth via different mechanisms,serving as attractive tools for tumor treatment either as a monotherapy or combining with other therapies for synergistic anti-tumor effects.In this critical review,we introduce the recent advances of bacteria-based tumor therapy from the following aspects.First,the general properties of bacteria are reviewed emphasizing on their structural components related to tumor immunotherapy,and the main bacteria that have been used in tumor therapy are listed.Then,the benefits of bacteria for tumor therapy are illustrated,such as tumor targetability,deep penetration,and facile genetic engineering for attenuation,enhanced efficacy,as well as bioimaging.Next,anti-tumor mechanisms of bacteria are summarized,which refer to intrinsic tumoricidal activities,immune activation,bacteria metabolism,and their capability to regulate gut microbiota homeostasis.Moreover,bacteria could act as carriers to deliver various types of therapeutics to achieve combination therapy with improved efficacy.In addition,several challenges for anti-tumor applications of bacteria are discussed regarding the delivery,efficacy and safety issues,and potential solutions are also provided.Finally,the possible improvements and perspectives are discussed in the end,which provide a guideline for the design of advanced bacteria-based tumor therapeutics in the future.

关键词： Bacteria Tumor targeting Immunotherapy Combination therapy Genetic engineering Surface decoration

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Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy

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Acta Pharmaceutica Sinica B 2023年第12期13卷 5074-5090页

作者： Lina Guo Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Key Laboratory of Biological Nanotechnology of National Health Commission Xiangya HospitalChangsha 410008China

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy.However,its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM).Here,we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO_(3))biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM regulator.CaCO_(3) can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading,and such biomineralization did not affect the bioactivities of the bacteria.Upon intratumoral accumulation,the CaCO_(3) shell was decomposed at an acidic microenvironment to atenuate tumor acidity,accompanied by the release of Sal and Ca^(2+)/A23187.Specifically,Sal served as a cancer vaccine producer by inducing cancer cells'immunogenic cell death(ICD)and promoting the gap junction formation between tumor cells and dendritic cells(DCs)to promote antigen presentation.Ca^(2+),on the other hand,was intermalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system,including DCs maturation,macrophages polarization,and T cells activation.As a result,such bio-vaccine achieved remarkable effcacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility.This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

关键词： Bacteria-mediated cancer therapy Tumor microenvironment Calcium carbonate Mineralization Metalloimmunology Autologous tumor vaccine Immunotherapy Tumor metastasis

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Macrophage-targeted nanomedicine for chronic diseases immunotherapy

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Chinese Chemical Letters 2022年第2期33卷 597-612页

作者： Yuejia Song Yaqian Huang Fang zhou Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Academician Workstation Changsha Medical UniversityChangsha 410219China Department of Pharmacy Southern University of Science and Technology HospitalShenzhen 518055China

Macrophage is the key innate immune effector in first-line defense against the pathogens, and can be polarized into different phenotypes to regulate a variety of immunological functions. However, the plasticity of macrophage is extraordinarily recruited, activated, and polarized under pathological conditions,playing paramount roles in occurrence, development, and prognosis of various chronic diseases, such as rheumatoid arthritis(RA), atherosclerosis(AS), and cancer. To this end, macrophage has become an important therapeutic target for etiological treatment of these diseases. Meanwhile, with the development of nanotechnology, various nano-drug delivery systems have been explored to target macrophages for disease modulation, displaying unique advantages to address both pharmaceutic and biopharmaceutic limitations of various drugs. This review aims to summarize the recent progress of macrophage-targeted nanomedicine for chronic diseases immunotherapy. First, the origin, polarization and biological functions of macrophages have been introduced, in which macrophages can differentiate into different phenotypes in response to physiological stimuli to play various immunological roles. Then, the macrophage disorder has been reviewed in related with various chronic diseases, and several representative diseases, including AS, RA, obesity, and cancer, have been discussed in detail to elucidate the pathological contributions of macrophages for disease progress. Next, strategies to regulate macrophages for diseases immunotherapy, such as macrophages depletion, macrophage reprograming, inhibition of macrophage recruitment,are summarized, and particular attention has been paid on bio-functional nanomaterials to engineer macrophages via different mechanisms. Further, methods for macrophage-targeting delivery nanosystems are discussed based on both passive and active targeting approaches. Finally, the perspective is speculated for potential clinical translation, and there still has significant room for the development of novel m

关键词： Nanoparticles Delivery Macrophages Polarization Immunotherapy

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Novel model of material removal rate on ultrasonic-assisted chemical mechanical polishing for sapphire

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摩擦:英文版 2023年第11期11卷 2073-2090页

作者： Mufang zhou Min ZHONG wenhu XU Department of Mechanical Engineering Key Laboratory of TribologyNanchang UniversityNanchang 330031China

Ultrasonic-assisted chemical mechanical polishing(UA-CMP)can greatly improve the sapphire material removal and surface quality,but its polishing mechanism is still unclear.This paper proposed a novel model of material removal rate(MRR)to explore the mechanism of sapphire UA-CMP.It contains two modes,namely two-body wear and abrasive-impact.Furthermore,the atomic force microscopy(AFM)in-situ study,computational fluid dynamics(CFD)simulation,and polishing experiments were conducted to verify the model and reveal the polishing mechanism.In the AFM in-situ studies,the tip scratched the reaction layer on the sapphire surface.The pit with a 0.22 nm depth is the evidence of two-body wear.The CFD simulation showed that abrasives could be driven by the ultrasonic vibration to impact the sapphire surface at high frequencies.The maximum total velocity and the air volume fraction(AVF)in the central area increased from 0.26 to 0.55 m/s and 20%to 49%,respectively,with the rising amplitudes of 1–3μm.However,the maximum total velocity rose slightly from 0.33 to 0.42 m/s,and the AVF was nearly unchanged under 40–80 r/min.It indicated that the ultrasonic energy has great effects on the abrasive-impact mode.The UA-CMP experimental results exhibited that there was 63.7%improvement in MRR when the polishing velocities rose from 40 to 80 r/min.The roughness of the polished sapphire surface was R_(a)=0.07 nm.It identified that the higher speed achieved greater MRR mainly through the two-body wear mode.This study is beneficial to further understanding the UA-CMP mechanism and promoting the development of UA-CMP technology.

关键词： sapphire ultrasonic-assisted chemical mechanical polishing(UA-CMP) material removal rate(MRR)predictive model atomic force microscopy(AFM)in-situ studies computational fluid dynamics(CFD)

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Macrophages-regulating nanomedicines for sepsis therapy

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Chinese Chemical Letters 2023年第3期34卷 100-112页

作者： Jiali Deng Rui Wang Shu Huang Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Department of Orthopedics Hunan Provincial People’s HospitalThe First-Affiliated Hospital of Hunan Normal UniversityChangsha 410005China

Sepsis is the leading cause of death in intensive care unit(ICU), which is caused by deregulated immune responses to pathogens infection. Clinically, sepsis treatment is limited to antibiotics and supportive care, while there still lacks of specific molecular therapy. As a type of immune dysfunction disease,macrophages have been recognized as the key immune cells precipitating in the whole process of sepsis,which is activated into M1-like to trigger various inflammatory responses at early stage whereas polarized into M2-like to cause immunosuppression in later stage. Therefore, great attention has been paid on the design of nanomedicines to regulate the functions of macrophages for etiological treatment of sepsis, by virtue of the unique advantages of nano-drug delivery systems, such as enhanced drug bioavailability, targetability, reduced side-effects. This critical review aims to summarize the recent progress of macrophages-regulating nanoparticles for sepsis therapy. First, the essential roles of macrophages in the development and progression of sepsis have been introduced, including the positive roles of macrophages to combat infections and dysfunction of macrophages to cause body damages. We then focus our main attention to discuss the nanomedicines with different therapeutic mechanisms corresponding to each stage of sepsis, such as infection blockage, inflammation inhibition, immune functions recovery, as well as multifunctional nanomedicines. Finally, a few limitations of current nanomedicines are highlighted,and future perspective are speculated for potential clinical translation, which might pave the way for the development of macrophages-centered nanomedicines for more effective sepsis therapy.

关键词： Nanomedicine Sepsis Macrophages Infections Inflammation Immunity

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Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer

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Asian Journal of Pharmaceutical Sciences 2022年第2期17卷 177-192页

作者： Peng Liu Ying Peng Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Henan Key Laboratory of Biomolecular Recognition and Sensing Shangqiu Normal UniversityShangqiu 476000China

Chemodynamic therapy(CDT)is considered as a promising modality for selective cancer therapy,which is realized via Fenton reaction-mediated decomposition of endogenous H_(2)O_(2) to produce toxic hydroxyl radical(•OH)for tumor ablation.While extensive efforts have been made to develop CDT-based therapeutics,their in vivo efficacy is usually unsatisfactory due to poor catalytic activity limited by tumor microenvironment,such as anti-oxidative systems,insufficient H_(2)O_(2),and mild acidity.To mitigate these issues,we have witnessed a surge in the development of CDT-based combinatorial nanomedicines with complementary or synergistic mechanisms for enhanced tumor therapy.By virtue of their bio-imaging capabilities,Fenton metal nanomedicines(FMNs)are equipped with intrinsic properties of imaging-guided tumor therapies.In this critical review,we summarize recent progress of this field,focusing on FMNs for imaging-guided combinatorial tumor therapy.First,various Fenton metals with inherent catalytic performances and imaging properties,including Fe,Cu and Mn,were introduced to illustrate their possible applications for tumor theranostics.Then,CDT-based combinatorial systems were reviewed by incorporating many other treatment means,including chemotherapy,photodynamic therapy(PDT),sonodynamic therapy(SDT),photothermal therapy(PTT),starvation therapy and immunotherapy.Next,various imaging approaches based on Fenton metals were presented in detail.Finally,challenges are discussed,and future prospects are speculated in the field to pave way for future developments.

关键词： combinatorial medicines equipped

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Copper carbonate nanoparticles as an effective biomineralized carrier to load macromolecular drugs for multimodal therapy

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中国化学快报:英文版 2023年第9期34卷 204-209页

作者： Liping Dong Jinsong Ding Lemei Zhu Yujun Liu Xiang Gao Wenhu Zhou Changsha Medical University Academician WorkstationChangsha 410219China Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and ToxicologyBeijing 100850China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410000China

Macromolecular drugs have attracted great interest as biotherapy to cure previously untreatable diseases.For clinical translation,biomacromolecules encounter several common druggability difficulties,such as in vivo instability and poor penetration to cross physiologic barriers,thus requiring sophisticated systems for drug delivery.Inspired by the natural biomineralization via interaction between inorganic ions and biomacromolecules,herein we rationally screened biocompatible transition metals to biomineralize with carbonate for macromolecules loading.Among the metal ions,Cu^(2+)was found to be the best candidate,and its superiority over the widely studied Ca^(2+)minerals was also demonstrated.Capitalized on this finding,copper carbonate nanoparticles were prepared via a simple mixing process to co-load glucose oxidase(GOx)and a HIF-αDNAzyme(DZ),achieving ultra-high loading capacity of 61%.Upon encapsulation into nanoparticles,enzymatic activity of both drugs was passivated to avoid potential side-effects during circulation,while the drugs could be rapidly released within 1 h in response to acidic p H to fully recover their activities.The nanoparticles could accumulate into tumor via intravenous injection,facilitate the cell membrane penetration,and release the payloads of GOx,DZ and Cu^(2+)inside cells to exert a series of anti-tumor effects.GOx caused tumor starvation by catalytic glucose consumption,and the concomitantly generated H_(2)O_(2)byproduct boosted the Cu^(2+)-mediated chemodynamic therapy(CDT).Meanwhile,the DZ silenced HIF-αexpression to sensitize both starvation therapy and CDT.As a result,a synergistic tumor growth inhibition was achieved.This work provides a simple method to prepare biomineralized nanoparticles,and offers a general approach for macromolecular drugs delivery via Cu^(2+)-based biomineralization.

关键词： Metal ions Biomineralization Drug delivery Nanomedicine Tumor therapy

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Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy

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Asian Journal of Pharmaceutical Sciences 2022年第4期17卷 557-570页

作者： Shengmei Wang Xuanjun Liu Minghua Yang Linqi Ouyang Jinsong Ding Shengfeng Wang Wenhu Zhou Department of Pharmacy The Third Xiangya HospitalCentral South UniversityChangshaHunan410013China Xiangya School of Pharmaceutical Sciences Central South UniversityChangshaHunan410013China Postdoctoral Research Station of Clinical Medicine and Department of Pediatrics The Third Xiangya HospitalCentral South UniversityChangshaHunan410013China The First Hospital of Hunan University of Chinese Medicine ChangshaHunan410007China

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metastasis.Here,we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities.The nanomedicine has a core-shell structure to co-load IPI549,a PI3Kγinhibitor,and CpG,a Toll-like receptor 9 agonist.Specifically,the hydrophobic IPI549 is self-assembled into a pure drug nano-core,while MOF shell layer is coated for CpG encapsulation,achieving extra-high total drugs loading of 44%.Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity,displaying excellent biocompatibility.After entering macrophages,the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype,which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines.Moreover,tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators,resulting in infiltration and activation of cytotoxic T lymphocytes.As a result,the nanosystem triggers a robust antitumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis.This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

关键词： Core-shell nanoparticles Metal-organic-framework CpG IPI549 Tumor immunotherapy

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A smart MnO_(2)-doped graphene oxide nanosheet for enhanced chemo-photodynamic combinatorial therapy via simultaneous oxygenation and glutathione depletion

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Acta Pharmaceutica Sinica B 2021年第3期11卷 823-834页

作者： Peng Liu Xin Xie Miao Liu Shuo Hu Jinsong Ding Wenhu Zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China School of Pharmaceutical Sciences Gannan Medical UniversityGanzhou 341000China Department of Nuclear Medicine Xiangya HospitalCentral South UniversityChangsha 410008China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410008China

The combination of chemotherapy and photodynamic therapy provides a promising approach for enhanced tumor eradication by overcoming the limitations of each individual therapeutic modality.However,tumor is pathologically featured with extreme hypoxia together with the adaptable overexpression of anti-oxidants,such as glutathione(GSH),which greatly restricts the therapeutic efficiency.Here,a combinatorial strategy was designed to simultaneously relieve tumor hypoxia by self-oxygenation and reduce intracellular GSH level to sensitize chemo-photodynamic therapy.In our system,a novel multifunctional nanosystem based on MnO_(2)-doped graphene oxide(GO)was developed to co-load cisplatin(Cis Pt)and a photosensitizer(Ce6).With Mn O_(2)doping,the nanosystem was equipped with intelligent functionalities:(1)catalyzes the decomposition of H_(2)O_(2)into oxygen to relieve the tumor hypoxia;(2)depletes GSH level in tumor cells,and(3)concomitantly generates Mn^(2+)to proceed Fenton-like reaction,all of which contribute to the enhanced anti-tumor efficacy.Meanwhile,the surface hyaluronic acid(HA)modification could facilitate the targeted delivery of the nanosystem into tumor cells,thereby resulting in amplified cellular toxicity,as well as tumor growth inhibition in nude mice model.This work sheds a new light on the development of intelligent nanosystems for synergistic combination therapy via regulating tumor microenvironment.

关键词： Cisplatin Nanoparticles Photosensitizer Tumor microenvironment Oxygenation GSH depletion Nanozyme Targeting

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