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Nanotechnology’s frontier in combatting infectious and inflammatory diseases:prevention and treatment

Signal Transduction and Targeted Therapy 2024年第3期9卷 998-1047页

作者： Yujing Huang Xiaohan Guo Yi Wu Xingyu Chen Lixiang Feng Na Xie Guobo Shen Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences and Forensic MedicineSichuan Universityand Collaborative Innovation Center for BiotherapyChengdu 610041China

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases,which continuously pose one of the most serious threats to human health,attributed to factors such as the emergence of new pathogens,increasing drug resistance,changes in living environments and lifestyles,and the aging population.Despite rapid advancements in mechanistic research and drug development for these diseases,current treatments often have limited efficacy and notable side effects,necessitating the development of more effective and targeted anti-inflammatory therapies.In recent years,the rapid development of nanotechnology has provided crucial technological support for the prevention,treatment,and detection of inflammation-associated diseases.Various types of nanoparticles(NPs)play significant roles,serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability.NPs can also directly combat pathogens and inflammation.In addition,nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases.This review categorizes and characterizes different types of NPs,summarizes their applications in the prevention,treatment,and detection of infectious and inflammatory diseases.It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects.In conclusion,nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

关键词： prevention inflammatory treatment

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Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses

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Acta Pharmaceutica Sinica B 2024年第2期14卷 821-835页

作者： Liping Bai Jin Yang Siting Yu Zhongzheng Xiang Yuanyuan Zeng Meiling Shen Xiaorong Kou Qinjie Wu Changyang Gong Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Radiotherapy(RT) can potentially induce systemic immune responses by initiating immunogenic cell death(ICD) of tumor cells.However,RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases.Herein,we construct multifunctional self-sufficient nanoparticles(MARS) with dual-enzyme activity(GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse.In addition to limiting the Warburg effect to actualize starvation therapy,MARS catalyzes glucose to produce hydrogen peroxide(H_(2)O_(2)),which is then used in the Cu^(+)-mediated Fenton-like reaction and RT sensitization.RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms,which have a robust ICD impact on mobilizing the immune system.Thus,when MARS is combined with RT,potent systemic antitumor immunity can be generated by activating antigen-presenting cells,promoting dendritic cells maturation,increasing the infiltration of cytotoxic T lymphocytes,and reprogramming the immuno suppre ssive tumor microenvironment.Furthermore,the synergistic therapy of RT and MARS effectively suppresses local tumor growth,increases mouse longevity,and results in a 90% reduction in lung metastasis and postoperative recurrence.Overall,we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

关键词： Dual-enzyme activity Radiotherapy Chemodynamic therapy Fenton-likereaction Radical storms Immunogeniccell death Tumormicroenvironment Systemicimmunity

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Drug delivery systems for colorectal cancer chemotherapy

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Chinese Chemical Letters 2024年第2期35卷 163-175页

作者： Wen Chen Kun Shi Yan Yu Peipei Yang Zhongwu Bei Dong Mo Liping Yuan Meng Pan Yu Chen Zhiyong Qian Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.

关键词： Colorectal cancer Chemotherapy Drug delivery systems Solubility Targeted Local administration

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Not to be and how not to be:the questions of Tregs controlled by RIPK1

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Cellular & Molecular Immunology 2024年第2期21卷 205-206页

作者： Zhengcai Peng Huiyuan Zhang Hongbo Hu center for Immunology and Hematology Department of Biotherapy and Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Chongqing International Institute for Immunology Chongqing401338China

Millions of cells undergo daily cell death,a process essential for maintaining physiological homeostasis and pathogenesis.Various forms of cell death,such as apoptosis,necroptosis,ferroptosis and pyroptosis,have been extensively studied for their distinct biological functions[1,2].Generally,programmed cell death,like apoptosis,is considered physiological and results in little to no inflammatory response.

关键词： death homeostasis pathogenesis

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Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

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Signal Transduction and Targeted Therapy 2024年第2期9卷 724-737页

作者： Zhengyu Yu Hexian Li Qizhong Lu Zongliang Zhang Aiping Tong Ting Niu Department of Hematology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)therapy.Current targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in relapse.Therefore,novel targets for enhancing CAR-T cell therapy in MM remain needed.Fc receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for MM.To further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome 1q21.Given the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and efficacy.Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression.Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

关键词： directed thereby offering

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Targeted drug approvals in 2023:breakthroughs by the FDA and NMPA

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Signal Transduction and Targeted Therapy 2024年第3期9卷 813-821页

作者： Lang Zheng Wenjing Wang Qiu Sun Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China Medical Publishers West China HospitalSichuan UniversityChengdu 610041China

According to the official website of China’s National Medicines and Pharmaceutical Administration(NMPA),a total of 87 novel drugs were approved in China in 2023,with targeted drugs accounting for 67.8%of the total,amounting to 59 drugs(Fig.1a;Table 1)[https://***/yaopin/ypjgdt/index.html].Notably,domestic innovation is flourishing,with five first-in-class drugs,including Glumetinib,a c-Met inhibitor from Haihe Biopharma;Leritrelvir,a 3CL protease inhibitor from Raynovent;Anaprazole,a proton pump inhibitor from Xuanzhu Biopharm;Pegol-Sihematide,an EPO drug from Hansoh Pharma;and Zuberitamab from BioRay Biopharmaceutical Co.,Ltd.Additionally,the world’s first allosteric inhibitor targeting TYK2,Sotyktu(deucravacitinib),has been approved for the treatment of psoriasis and Selumetinib,a MEK inhibitor co-developed by AstraZeneca and Merck Sharp&Dohme(MSD),became the first approved drug in China for the treatment of neurofibromatosis type I(NF1).Beyond these drugs,the approval of novel drug types such as CAR-T cell products,siRNA,monoclonal antibodies,dual antibodies,and ADCs in China is a significant development in the country’s pharmaceutical industry(Fig.1a).

关键词： drugs Merck approval

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Structural analysis of conformational changes in the mpox virus A7 protein

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Virologica Sinica 2024年第2期39卷 331-334页

作者： Xincheng Ni Kai Wang Yinze Han Jian Lei National Clinical Research center for Geriatrics and State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China

Dear Editor,The mpox(formerly known as monkeypox)disease caused by the mpox virus(MPXV)has infected more than 89,700 people and is linked to 157 deaths in 114 countries worldwide as of September 2023(www.***.int).Mpox is a zoonotic disease,the first human case of which was reported in 1970(Breman et al.,1980).Common symptoms in mpox-infected individuals include fever,myalgia,fatigue,headache,and a characteristic rash(Isidro et al.,2022).Current treatments for mpox remain limited,and an in-depth investigation of essential viral protein(s)will help to explore novel drug targets.

关键词： infected headache

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Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes

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中华医学杂志(英文版) 2024年第7期137卷 791-805页

作者： Cui Daxin Feng Xingrong Lei Siman Zhang Hongmei Hu Wanxin Yang Shanshan Yu Xiaoqian Su Zhiguang Molecular Medicine Research center and Department of Endocrinology and Metabolism West China Hospital Sichuan University Chengdu Sichuan 610041 China State Key Laboratory of biotherapy Clinical Translational Innovation center

Pancreatic β-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing β-cells and hence restoring insulin production are gaining attention in translational diabetes research, and β-cell replenishment has been the main focus for diabetes treatment. Significant findings in β-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate β-cells. In this review, we summarize current knowledge on the mechanisms implicated in β-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to β-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting β-cell proliferation, inducing non-β-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for β-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous β-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

关键词： Pancreatic β-cell regeneration Diabetes Insulin Dedifferentiation Transdifferentiation Stem cell

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Intranasal boosting with RBD-HR protein vaccine elicits robust mucosal and systemic immune responses

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Genes & Diseases 2024年第4期11卷 327-339页

作者： Li Chen Wenyan Ren Hong Lei Jiayu Wang Haiying Que Dandan Wan Aqu Alu Dandan Peng Minyang Fu Weiqi Hong Yuhe Huang Xiangrong Song Guangwen Lu Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610041China

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.

关键词： Heterologous immunization Intranasal immunization mRNA vaccine SARS-CoV-2 Subunitprotein vaccine

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Lung microbiome:new insights into the pathogenesis of respiratory diseases

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Signal Transduction and Targeted Therapy 2024年第2期9卷 652-678页

作者： Ruomeng Li Jing Li Xikun Zhou Department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuan 610041China

The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community.The microbiome of healthy lungs is mainly derived from the upper respiratory tract(URT)microbiome but also has its own characteristic flora.The selection mechanisms in the lung,including clearance by coughing,pulmonary macrophages,the oscillation of respiratory cilia,and bacterial inhibition by alveolar surfactant,keep the microbiome transient and mobile,which is different from the microbiome in other organs.The pulmonary bacteriome has been intensively studied recently,but relatively little research has focused on the mycobiome and virome.This up-to-date review retrospectively summarizes the lung microbiome’s history,composition,and function.We focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune responses.More importantly,we focus on multiple respiratory diseases,including asthma,chronic obstructive pulmonary disease(COPD),fibrosis,bronchiectasis,and pneumonia.The impact of the lung microbiome on coronavirus disease 2019(COVID-19)and lung cancer has also been comprehensively studied.Furthermore,by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field,we propose an outlook of the direction of lung microbiome research.

关键词： respiratory diseases Lung

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