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cancer immunotherapy with envelopedself-amplifying mRNA CARG-2020 thatmodulates IL-12,IL-17 and PD-L1 pathways toprevent tumor recurrence

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Acta Pharmaceutica Sinica B 2024年第1期14卷 335-349页

作者： Ju Chen Bhaskara Reddy Madina Elham Ahmadi Timur Olegovich Yarovinsky Marie Marthe Krady Eileen Victoria Meehan Isabella China Wang Xiaoyang Ye Elise Pitmon Xian-Yong Ma Bijan Almassian Valerian Nakaar Kepeng Wang Department of Immunology School of MedicineUniversity of Connecticut Health CenterFarmingtonCT 06030USA CaroGen Corporation FarmingtonCT 06030USA The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine Foshan Hospital of Traditional Chinese MedicineFoshan 528000China The Loomis Chaffee School WindsorCT 06095USA

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for ***,we describe the application of virus-like vesicles(VLV)for delivery of three immunomodulators alone and in combination,as a promising approach for cancer *** vectors were designed to deliver single chain interleukin(IL)-12,shorthairpin RNA(shRNA)targeting programmed death ligand 1(PD-L1),and a dominant-negative form of IL-17 receptor A(dn-IL17RA)as a single payload or as a combination *** delivery of the VLV vector expressing IL-12 alone,as well as the trivalent vector(designated CARG-2020)eradicated large established ***,only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice,indicating a benefit of the combined *** abscopal effects of CARG-2020 on the non-injected contralateral tumors,as well as protection from the tumor cell re-challenge,suggest immune-mediated mechanism of protection and establishment of immunological ***,CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting *** ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

关键词： Virus-like vesicles Oncolytic virus IL-12 IL-17 PD-L1 T cell exhaustion Combination therapy cancer immunotherapy

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Natural long-chain saturated fatty acids doped LNPs enabling spleen selective mRNA translation and potent cancer immunotherapy

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Nano Research 2024年第3期17卷 1804-1817页

作者： Fazhan Wang Meng Zhang Meiling Tian Jia Lou Longze Pan Xiaoke Gao Lijing Zhang Xiaohan Lou Linyu Zhu Yuqiao Sheng Ming Wang Rui Xue Wenjing Deng Shuai Shao Zhihai Qin Medical Research Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Translational Medical Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Department of Neuro-Intensive Care Unit The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Academy of Medical Sciences Zhengzhou UniversityZhengzhou 450052China

Rationally tailored lipid nanoparticles(LNPs)with efficient and tunable delivery of mRNA in vivo are crucial for mRNA *** expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA *** by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver,we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered *** the molar ratio of saturated fatty acid located 60%–70%,the doped LNPs achieved the spleen selective mRNA *** mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in *** with a model antigen(ovalbumin)mRNA-loaded spleen selective LNPs,we observed enhanced antigen-specific T cell immune responses,and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma *** natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.

关键词： mRNA vaccine lipid nanoparticles spleen long-chain saturated fatty acid cancer immunotherapy

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Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy

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Nano Research 2024年第8期17卷 7357-7364页

作者： Kai Xu Yujia Xu Jin Sun Xinwei Cheng Chenxi Lu Wenzhong Chen Bingfang He Tianyue Jiang School of Pharmaceutical Sciences Nanjing Tech UniversityNanjing 211816China Department of Nano Formulation Nanjing GeneLeap BiotechnologyNanjing 210061China

Messenger ribonucleic acid(mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles(LNPs)are the most extensively applied non-viral platform for RNA delivery in *** the clinical success of LNPs as vehicles have been achieved,developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and *** this study,we designed a series of new ionizable amino lipids with piperazinederived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA *** them,LNP formulated with lipid 10(L10-LNP)can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo,which is mainly attributed to the improved intracellular uptake and effective endosomal *** verified that a single administration of L10-LNP packaging interleukin(IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8^(+)T cells and stimulating the generation of IFN-γwithout causing systemic toxicity,which provides a promising platform for clinical cancer immunotherapy.

关键词： ionizable lipid lipid nanoparticle piperazine-derived lipid mRNA therapeutics cancer immunotherapy

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NIR-Ⅱ responsive Janus nanoparticles amplify immunogenic cell death for enhanced cancer immunotherapy

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Science China(Technological Sciences) 2024年第1期67卷 321-329页

作者： CHEN BeiBei GUO KangLi WANG HaoRan XU Fu-Jian WANG JuLin ZHAO NaNa State Key Laboratory of Chemical Resource Engineering Beijing University of Chemical TechnologyBeijing 100029China Key Laboratory of Biomedical Materials of Natural Macromolecules(Beijing University of Chemical Technology) Beijing Laboratory of Biomedical MaterialsBeijing University of Chemical TechnologyBeijing 100029China College of Materials Sciences and Engineering Beijing University of Chemical TechnologyBeijing 100029China Beijing Key Laboratory of Electrochemical Process and Technology for Materials Beijing University of Chemical TechnologyBeijing 100029China

immunotherapy brings new hope for tumor treatment by inducing immunogenic cell death(ICD)of tumor ***,insufficient immunogenicity and low immune response rate greatly limit antitumor ***,by optimizing the composition and morphology,the rational design of Janus nanoparticles composed of Fe_(3)O_(4) nanospheres and SiO_(2)nanorods was realized for enhanced cancer immunotherapy through amplified *** glucose oxidase(GOx)was loaded by the Janus nanoparticles,the resultant M-FS-GOx consumes glucose at tumor sites to generate gluconic acid and hydrogen peroxide(H_(2)O_(2))for starvation therapy while the H_(2)O_(2)supply promotes the production of highly toxic·OH to achieve effective chemodynamic therapy(CDT).Under a 1064 nm light irradiation,the photothermal effect of M-FS-GOx enhances the enzyme activity of GOx for improved starvation ***,both tumor-associated antigens released during the process of ICD and the intrinsic immunoadjuvant property of M-FS-GOx stimulate dendritic cell maturation to activate antitumor immune *** work provides a promising strategy for the construction of Janus nanoparticles to achieve enhanced cancer immunotherapy through combination therapy-amplified ICD.

关键词： Janus nanoparticles immunogenic cell death cancer immunotherapy

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Bionic immunoactivator copresenting autophagy promoting and costimulatory molecules for synergistic cancer immunotherapy

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Nano Research 2024年第3期17卷 1710-1724页

作者： Yiwei Peng Yiliang Yang Zhenzhen Yang Datong Gao Jiajia Li Qi Sun Yitian Du Meng Lin Xianrong Qi Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System School of Pharmaceutical SciencesPeking UniversityBeijing 100191China

immunotherapy has great promise in improving malignant tumor ***,the efficacy of existing strategies is often limited by the immunosuppressive ***,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune ***-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor ***-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive ***-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold *** group)in mouse tumor model after intravenous or subcutaneous ***,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and *** findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor *** these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.

关键词： in situ bionic immunoactivator autophagy glucocorticoid-induced tumor necrosis factor receptor(GITR)agonist platelets and platelet microparticles cancer immunotherapy

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Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1525-1541页

作者： Qi Shang Wandong Liu Faith Leslie Jiapei Yang Mingmei Guo Mingjiao Sun Guangji Zhang Qiang Zhang Feihu Wang School of Biomedical Engineering Shanghai Jiao Tong UniversityShanghai 200240China School of Basic Medical Sciences Zhejiang Chinese Medical UniversityHangzhou 310053China Key Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province Hangzhou 310053China Department of Chemical and Biomolecular Engineering Whiting School of Engineeringthe Johns Hopkins UniversityBaltimoreMD 21218USA Traditional Chinese Medicine“Preventing Disease”Wisdom Health Project Research Center of Zhejiang Hangzhou 310053China Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

cancer immunotherapy has garnered promise in tumor progression, invasion, and metastasis through establishing durable and memorable immunological activity. However, low response rates, adverse side effects, and high costs compromise the additional benefits for patients treated with current chemical and biological agents. Chinese herbal medicines (CHMs) are a potential treasure trove of natural medicines and are gaining momentum in cancer immunomodulation with multi-component, multi-target, and multi-pathway characteristics. The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms. Additionally, the introduction of nanotechnology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity, stability, permeability, and targeting characteristics, further enhancing anti-cancer immunity. In this review, we summarize the mechanism of active ingredients for cancer immunomodulation, highlight nano-formulated deliveries of active ingredients for cancer immunotherapy, and provide insights into the future applications in the emerging field of nano-formulated active ingredients of CHMs.

关键词： Chinese herbal medicines Nano-formulation Activeingredients Drug delivery cancer immunotherapy Innate immune system Adaptive immune system

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Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy

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Science China(Life Sciences) 2024年第5期67卷 996-1009页

作者： Xiaowen Zhou Yang Li Xiangrui Zhang Beibei Li Shengzhe Jin Menghan Wu Xiuman Zhou Qingyu Dong Jiangfeng Du Wenjie Zhai Yahong Wu Lu Qiu Guodong Li Yuanming Qi Wenshan Zhao Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China

The immune checkpoint TIGIT/PVR blockade exhibits significant antitumor effects through activation of NK and CD8^(+)T cell-mediated *** checkpoint blockade(ICB)could induce tumor ferroptosis through IFN-γreleased by immune cells,indicating the synergetic effects of ICB with ferroptosis in inhibiting tumor ***,the development of TIGIT/PVR inhibitors with ferroptosis-inducing effects has not been explored *** this study,the small molecule Hemin that could bind withTIGIT to block TIGIT/PVR interaction was screened by virtual molecular docking and cell-based blocking *** could effectively restore the IL-2 secretion from Jurkat-hTIGIT *** reinvigorated the function of CD8^(+)T cells to secrete IFN-γand the elevated IFN-γcould synergize with Hemin to induce ferroptosis in tumor *** inhibited tumor growth by boosting CD8^(+)T cell immune response and inducing ferroptosis in CT26 tumor *** importantly,Hemin in combination with PD-1/PD-L1 blockade exhibited more effective antitumor efficacy in anti-PD-1 resistant B16 tumor *** summary,our finding indicated that Hemin blocked TIGIT/PVR interaction and induced tumor cell ferroptosis,which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

关键词： cancer immunotherapy TIGIT/PVR small molecule Hemin ferroptosis

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Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1150-1165页

作者： Yuzhen Qian Yixuan Sun Peishang Shi Xiuman Zhou Qiongqiong Zhang Qingyu Dong Shengzhe Jin Lu Qiu Xiaoshuang Niu Xiaowen Zhou Wenshan Zhao Yahong Wu Wenjie Zhai Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China International Joint Laboratory for Protein and Peptide Drugs of Henan Province Zhengzhou UniversityZhengzhou 450001China

Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower ***-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/***,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in ***,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ *** importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune *** conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

关键词： LAG-3 FGL1 PD-1 PD-L1 Peptide Immune checkpoint Radiotherapy cancer immunotherapy

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M1-polarized macrophage-derived cellular nanovesicle-coated lipid nanoparticles for enhanced cancer treatment through hybridization of gene therapy and cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3169-3183页

作者： Ha Eun Shin Jun-Hyeok Han Seungyong Shin Ga-Hyun Bae Boram Son Tae-Hyung Kim Hee Ho Park Chun Gwon Park Wooram Park Department of Integrative Biotechnology Sungkyunkwan University(SKKU)SuwonGyeonggi 16419Republic of Korea Deparment of Inteligent Precision Healthcare Convergence SKKUSuwonGyeonggi 16419Republic of Korea Department of MetaBioHealth SKKU Institute for ConvergenceSKKUSuwonGyeonggi 16419Republic of Korea Department of Bioengineering Hanyang UniversitySeoul 04763Republic of Korea Department of Integrative Engineering Chung-Ang UniversitySeoul 06974Republic of Korea Department of Biomedical Engineering SKKUSuwonGyeonggi 16419Republic of Korea Korea Institute of Science and Technology(KIST) Seoul 02792Republic of Korea

Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene *** nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 *** study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid *** dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor *** retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth *** findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.

关键词： Genetic-immunotherapy M1 macrophage-derived cellular nanovesicles Lipid nanoparticles(LNPs) Gene therapy siRNA cancer immunotherapy Solid tumor Tumor microenvironment(TME)

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Emerging mechanisms and implications of c GAS-STING signaling in cancer immunotherapy strategies

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cancer Biology & Medicine 2024年第1期21卷 45-64页

作者： Jiawen Zhang Sihui Yu Qiao Peng Ping Wang Lan Fang Tongji University cancer Center Shanghai Tenth People’s HospitalSchool of MedicineTongji UniversityShanghai 200072China Reproductive Medicine Center Department of Obstetrics and GynecologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 201620China Department of Obstetrics and Gynecology Zhongshan HospitalFudan UniversityShanghai 200032China

The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer *** this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key *** cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor ***,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer *** strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint *** approaches have shown promise in preclinical and clinical settings,by enhancing patient survival *** review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and ***,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy *** challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.

关键词： cGAS-STING pathway type I interferon cyclic dinucleotide STING agonist cancer immunotherapy

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