Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy ha...Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy has shown potential to inhibit recurrence and metastasis,the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments.The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells(TIDCs)which leads to an inferior immune response to distant tumor growth and metastasis.Herein,an antigen-capturing nanoplatform,whose surface was modified with mannose as a targeting ligand,was constructed for co-delivering tumor-associated antigens(TAAs)and m6A demethylases inhibitor(i.e.,fat mass and obesity asso-ciated gene(FTO)inhibitor)into TIDCs.In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells(DCs)maturation,improves tumor infiltration of effector T cells and generates immune memory,which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis.Therefore,the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.展开更多
Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macr...Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity,which leads to microflora disturbance,destructive periodontal inflammation and alveolar bone loss eventually.Here,an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages(named ex-situ macrophages hereafter)and a complement C5a receptor antagonist(C5A)to the gingival crevice.Through appropriately tuning the hydrogel stiffness,the phagocytic activity of these macrophages is greatly enhanced,reaching an optimal performance at the elastic modulus of 106 kPa.Meanwhile,C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages.Besides,the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche,which contributes to the alleviated periodontal inflammation and attenuated bone loss as well.This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells,which is expected to find wide applications even beyond periodontitis treatment.展开更多
基金National Natural Science Foundation of China(51933011,31971296,52173125,82102194,81873920,82001930)Key Areas Research and Development Program of Guangzhou(202007020006)+2 种基金Natural Science Foundation of the Guangdong Province(2021A1515010250,2020A1515111206,2021A1515111006)China Postdoctoral Science Foundation(2020M680119,2021M703763)Funding of the Southern Medical University Nanfang Hospital(2019C015).
文摘Thermal ablation(TA)as an effective method treating hepatocellular carcinoma(HCC)in clinics is facing great challenges of high recurrence and metastasis.Although immune-checkpoint blockade(ICB)-based immuno-therapy has shown potential to inhibit recurrence and metastasis,the combination strategy of ICB and thermal ablation has shown little progress in HCC treatments.The tremendous hurdle for combining ICB with thermal ablation lies with the insufficient antigen internalization and immaturity of tumor-infiltrating dendritic cells(TIDCs)which leads to an inferior immune response to distant tumor growth and metastasis.Herein,an antigen-capturing nanoplatform,whose surface was modified with mannose as a targeting ligand,was constructed for co-delivering tumor-associated antigens(TAAs)and m6A demethylases inhibitor(i.e.,fat mass and obesity asso-ciated gene(FTO)inhibitor)into TIDCs.In vivo results demonstrate that the intratumoral injection of nanodrug followed by HCC thermal ablation promotes dendritic cells(DCs)maturation,improves tumor infiltration of effector T cells and generates immune memory,which synergize with ICB treatment to inhibit the distant tumor growth and lung metastasis.Therefore,the antigen-capturing and FTO-inhibiting nanodrug holds potential to boost the ICB-based immunotherapy against HCC after thermal ablation.
基金This work was supported by the National Natural Science Foundation of China(82170987,81970963,51933011,31971296)the Natural Science Foundation of Guangdong Province(2021A1515012535)the General Scientific Research Cultivation Project of Guanghua School of Stomatology,Sun Yat-Sen University(174-2018-XMZC-0001-03-0125/D-16).
文摘Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity,which leads to microflora disturbance,destructive periodontal inflammation and alveolar bone loss eventually.Here,an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages(named ex-situ macrophages hereafter)and a complement C5a receptor antagonist(C5A)to the gingival crevice.Through appropriately tuning the hydrogel stiffness,the phagocytic activity of these macrophages is greatly enhanced,reaching an optimal performance at the elastic modulus of 106 kPa.Meanwhile,C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages.Besides,the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche,which contributes to the alleviated periodontal inflammation and attenuated bone loss as well.This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells,which is expected to find wide applications even beyond periodontitis treatment.